Mammalian genes; related reagents

ABSTRACT

Purified nucleic acids encoding C1QSF3 from a mammal, purified C1QSF3 proteins, specific antibodies thereto, and related reagents are provided. Methods of using these molecules and reagents are also provided.

[0001] This application claims benefit of U.S. Provisional Patent Application No. 60/317,988, filed Sep. 6, 2001.

FIELD OF THE INVENTION

[0002] The present invention pertains to compositions related to proteins which function in controlling activation and expansion of mammalian cells, e.g., cells of a mammalian immune system. In particular, it provides purified genes, proteins, antibodies, and related reagents useful, e.g., to regulate activation, development, differentiation, and function of various cell types, including hematopoietic cells.

BACKGROUND OF THE INVENTION

[0003] Proteins of the Tumor Necrosis Factor (TNF) and the complement C1q families share structural and functional similarities. The TNF and C1q families share certain conserved amino acid residues, a common folding topology, i.e., globular C1q (gC1q) domain, and similar gene structures (Kishore and Reid (1999) Immunopharmacol. 42:15-21). Both groups of proteins appear to play major roles in immunity as well as in energy homeostasis.

[0004] Typical TNF family molecules involved in immunity include CD40L, TNFα, and FAS ligand (see, e.g., Tracey and Cerami (1994) Annu. Rev. Med. 45:491-503). CD40L knockout mice are defective in antibody class switching and lack all immunoglobulins except IgM in the T-dependent humoral response (see, e.g., Renshaw, et al. (1994) J. Exp. Med. 180:1889-1900). Similarly, C1q knockout mice also exhibit defects in class switching (see, e.g., Shapiro and Scherer (1998) Curr. Biol. 8:335-338). This suggests that these structurally related molecules may play similar roles.

[0005] Like many complement proteins, TNFα is produced in response to infection and effects multiple responses, including inflammation, cell proliferation, and cell death acting via TNF receptors (see, e.g., Tracey and Cerami, supra). TNFα has also been shown to regulate the expression levels of some downstream components of the complement system (see, e.g., Kulics, et al. (1994) Immunology 82:509-515; and Kawakami, et al. (1997) Cancer Letts. 116:21-26). TNF also plays a role in energy homeostatis, where it is implicated in cachexia, obesity, and insulin resistance (see, e.g., Hotamislgil and Spiegelman (1994) Diabetes 1271-1278; and Teoman, et al. (1997) 389:610-614). It also is a major secretory product of adipocytes (see, e.g., Hotamislgil and Speigelman, supra.).

[0006] Similar activities have been observed for C1q family proteins. For example, ACRP30 is made exclusively in adipocytes and its expression is dysregulated in various forms of obesity. ACRP30 secretion is acutely stimulated by insulin and repressed by chronically elevated levels of insulin (see, e.g., Shapiro and Scherer, supra). Another C1q-like molecule, the Hib27 molecule from Siberian chipmunks, also seems to be involved in energy homeostasis, as its expression is specifically extinguished during hibernation (see, e.g., Takamatsu, et al. (1993) Mol. Cell. Biol. 13:1516-1521). The functional connection between adipose tissue and immunity has been noted before: adipocytes secrete high levels of complement factors C3 and B, and provide the unique site of synthesis for complement factor D (see, e.g., Flier, et al. (1987) Science 237:405-408).

[0007] C1q is the first subcomponent of the C1 complex of the classical pathway of complement activation. C1q plays a key role in the recognition of immune complexes. The molecule consists of several structural chains and domains, including a C-terminal globular region (gC1q domain) of approximately 135 residues (see, e.g., Sellar et al. (1991) Biochem. J. 274:481-490). Several molecules that contain the gC1q domain have been identified and placed in a new category of structurally similar molecules known as the C1q/TNF superfamily. Included in this group of molecules are precerebellin, multimerin, EMILIN, C1qA, C1qB, C1qC, Acrp-30, HP, Type X collagen, Type VIII collagen, and saccular collagen.

[0008] Recently, it has been observed that C1q containing molecules are seen in Lewy bodies, oligodendroglia, and the substantia nigra in cells from Parkinson's disease brain tissue. Also present in these tissues are increased levels of TNFCC and other cytokines (see, e.g., McGeer, et al. (2001) BC Med. J. 43:138-141). It is known that in patients suffering from Parkinson's disease, there is an increase in microglial cells, which are the main immune defense in the brain. C1q containing proteins can activate these cells (see, e.g., McGeer, et al. supra.) Further studies have revealed that TNF and C1Q containing molecules are involved in the disease progression of a number of inflammatory diseases, e.g., inflammatory bowel disease, Crohn's disease, skin inflammation, psoriasis, and Hashimoto's thyroiditis (See, e.g., Federici, et al. (2002) J. Immunol. 169:434-442; Suzuki, et al. (2001) J. Exp. Med. 193:471-482; Aust, et al. (1996) Clin. Exp. Immunol. 105:148-154).

[0009] A number of pathways that regulate inflammation or energy metabolism have been identified, where these pathways involve proteins of the TNF/C1q superfamily. However, the molecules and interactions responsible for inflammation and energy metabolism are only partially understood. The present invention fulfills this need by identifying a new member of the TNF/C1q superfamily.

BRIEF DESCRIPTION OF THE DRAWING

[0010] FIGS. 1A-D shows an alignment of TNF/C1Q superfamily members and the molecules of the present invention. Boxes indicate β-strands, and shaded areas are structural domains as predicted by XTAL.

SUMMARY OF THE INVENTION

[0011] The present invention is based, in part, upon the discovery of a molecule that has structural similarity to TNF/C1q superfamily members. In particular, it provides polypeptides, polynucleotides, binding compositions, methods of production, methods of use, and kits.

[0012] The present invention provides an isolated nucleic acid encoding a polypeptide comprising SEQ ID NO:10 or 12, or an antigenic fragment thereof. Also provided is an isolated nucleic acid which hybridizes to a nucleic acid encoding a polypeptide comprising SEQ ID NO:10 or 12, or an antigenic fragment thereof, under stringent conditions. The invention encompasses an isolated nucleic acid comprising SEQ ID NO:9 or 11. Additionally provided is an expression or replicating vector comprising a nucleic acid encoding a polypeptide comprising SEQ ID NO:10 or 12, or an antigenic fragment thereof. The invention also encompasses a host cell comprising an expression or replicating vector comprising a nucleic acid encoding a polypeptide comprising SEQ ID NO:10 or 12, or an antigenic fragment thereof.

[0013] The invention provides an isolated polypeptide comprising SEQ ID NO:10 or 12, or an antigenic fragment thereof. The invention also provides an isolated polypeptide comprising SEQ ID NO:10 or 12, or an antigenic fragment thereof, further comprising a fusion polypeptide or peptide.

[0014] The invention provides a binding composition which specifically binds to a polypeptide comprising SEQ ID NO:10 or 12, or an antigenic fragment thereof. The invention also encompasses a binding composition which specifically binds to an isolated polypeptide comprising SEQ ID NO:10 or 12, or an antigenic fragment thereof, where the binding composition may comprise an antigen binding site of an antibody, or where the antigen binding site may be a polyclonal antibody, monoclonal antibody, humanized antibody, Fab fragment, F(ab′)₂ fragment, or Fv fragment, or where the antigen binding site is detectably labeled.

[0015] Also encompasses is a binding composition which specifically binds to a polypeptide comprising SEQ ID NO:10 or 12, or an antigenic fragment thereof, in conjunction with an acceptable carrier. Also provided is a kit comprising a substantially pure polypeptide comprising SEQ ID NO:10 or 12, or an antigenic fragment thereof, a binding composition which specifically binds the polypeptide; or a nucleic acid encoding the polypeptide.

[0016] Additionally, the invention provides a method of producing a polypeptide comprising SEQ ID NO:10 or 12, or an antigenic fragment thereof, comprising culturing a host cell comprising an expression or replicating vector comprising a nucleic acid encoding a polypeptide comprising SEQ ID NO:10 or 12 under conditions suitable for expression of the polypeptide, and isolating or purifying the polypeptide. Also provided is a method of modulating the activity of a cell comprising contacting the cell with a binding composition which specifically binds to the polypeptide comprising SEQ ID NO:10 or 12, or an antigenic fragment thereof.

[0017] The invention encompasses a method of treating a subject suffering from an inflammatory condition comprising administering an effective amount of an agonist or antagonist of a polypeptide comprising SEQ ID NO:10 or 12, or an antigenic fragment thereof. Also encompassed is a method of treating a subject suffering from an inflammatory condition comprising administering an effective amount of an agonist or antagonist of a polypeptide comprising SEQ ID NO:10 or 12, or an antigenic fragment thereof, where the agonist or antagonist is a binding composition which specifically binds to a polypeptide comprising SEQ ID NO:10 or 12, or an antigenic fragment thereof.

DETAILED DESCRIPTION

[0018] As used herein, including the appended claims, the singular forms of words such as “a,” “an,” and “the,” include their corresponding plural references unless the context clearly dictates otherwise.

[0019] All references cited herein are incorporated herein by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0020] I. Definitions.

[0021] “Activity” of a molecule may describe or refer to binding of the molecule to a ligand or to a receptor, to catalytic activity, to the ability to stimulate gene expression, to antigenic activity, to the modulation of activities of other molecules, and the like. “Activity” of a molecule may also refer to activity in modulating or maintaining cell-to-cell interactions, e.g., adhesion, or activity in maintaining a structure of a cell, e.g., cell membranes or cytoskeleton. “Activity” may also mean specific activity, e.g., [catalytic activity]/[mg protein], or [immunological activity]/[mg protein], or the like.

[0022] “Amino acid” refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, including selenomethionine, as well as those amino acids that are modified after incorporation into a polypeptide, e.g., hydroxyproline, γ-carboxyglutamate, O-phosphoserine, and cystine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an alpha-carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. “Amino acid mimetics” refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. Amino acids may be referred to herein by either their commonly known three letter symbols or by their one-letter symbols.

[0023] “Antibody” refers to a polypeptide comprising a framework region from an immunoglobulin gene or fragments thereof that specifically binds and recognizes an antigen. The immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.

[0024] Antibodies exist, e.g., as intact immunoglobulins or as a number of well-characterized fragments produced by digestion with various peptidases. Thus, for example, pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)′₂, a dimer of Fab which itself is a light chain joined to V_(H)-C_(H)1 by a disulfide bond. The F(ab)′₂ may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab)′₂ dimer into an Fab′ monomer. The Fab′ monomer is essentially Fab with part of the hinge region.

[0025] “Fv” fragment comprises a dimer of one heavy chain and one light chain variable domain in tight association with each other. A single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site (Paul (ed) (1993) Fundamental Immunology, Third Ed., Raven Press, New York).

[0026] The term “monoclonal antibody” (mAb) refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibody polypeptides comprising the population are identical except for possible naturally occurring mutations in the polypeptide chain that may be present in minor amounts. The term “monoclonal antibody” does not suggest any characteristic of the oligosaccharide component, or that there is homogeneity or heterogeneity with regard to oligosaccharide component. Monoclonal antibodies are highly specific, being directed against a single antigenic site or epitope. In contrast to conventional (polyclonal) antibody preparations which typically include different antibodies directed against different epitopes, each mAb is directed against a single determinant on the antigen. In addition to their specificity, the monoclonal antibodies are advantageous in that they can be synthesized by hybridoma culture, uncontaminated by other immunoglobulins. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. “Monoclonal antibodies” also include clones of antigen-recognition and binding-site containing antibody fragments, such as those derived from phage antibody libraries.

[0027] “Diabodies” refers to a fragment comprising a heavy chain variable domain (V_(H)) connected to a light chain variable domain (V_(L)) (Hollinger, et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448).

[0028] “Binding composition” refers to a molecule, small molecule, macromolecule, antibody, or a fragment or analog, thereof, which is capable of binding to a target. “Binding composition” also may refer to a complex of molecules, e.g., a non-covalent complex, to an ionized molecule, and to a covalently or non-covalently modified molecule, e.g., modified by phosphorylation, acylation, cross-linking, or cyclization, which is capable of binding to a target. “Binding composition” may also refer to a molecule capable of binding to a target in combination with a stabilizer, excipient, salt, buffer, solvent, or additive. “Binding” may be defined as an association of the binding composition with a target where the normal Brownian motion of the binding composition is prevented or impaired, in cases where the binding composition can be dissolved or suspended in solution.

[0029] “Cell line” refers to a population of cells capable of continuous or prolonged growth and division in vitro. Often, cell lines are clonal populations derived from a single progenitor cell. Spontaneous or induced changes can occur in the genome or can occur during storage or transfer of one or more cells present in the population of cells. Therefore, cells derived from the cell line referred to may not be precisely identical to the ancestral cells or cultures, and the cell line referred to includes such variants. The term “cell line” also includes immortalized cells (U.S. Pat. No. 6,090,611 issued to Covacci, et al.).

[0030] “Conservatively modified variants” applies to both amino acid and nucleic acid sequences. With respect to particular nucleic acid sequences, conservatively modified variants refers to those nucleic acids which encode identical or essentially identical amino acid sequences, or where the nucleic acid does not encode an amino acid sequence, to essentially identical nucleic acid sequences. Because of the degeneracy of the genetic code, a large number of functionally identical nucleic acids encode any given protein.

[0031] As to amino acid sequences, one of skill will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds or deletes a conserved amino acid or a small percentage of amino acids in the encoded sequence is a “conservatively modified variant.” Conservative substitution tables providing functionally similar amino acids are well known in the art. An example of a conservative substitution is the exchange of an amino acid in one of the following groups for another amino acid of the same group (U.S. Pat. No. 5,767,063 issued to Lee, et al.; Kyte and Doolittle (1982) J. Mol. Biol. 157:105-132):

[0032] (1) Hydrophobic: Norleucine, Ile, Val, Leu, Phe, Cys, or Met;

[0033] (2) Neutral hydrophilic: Cys, Ser, Thr;

[0034] (3) Acidic: Asp, Glu;

[0035] (4) Basic: Asn, Gln, His, Lys, Arg;

[0036] (5) Residues that influence chain orientation: Gly, Pro;

[0037] (6) Aromatic: Trp, Tyr, Phe;

[0038] (7) Small amino acids: Gly, Ala, Ser.

[0039] “Exogenous” refers to substances that are produced outside an organism or cell, depending on the context. “Endogenous” refers to substances that are produced within a cell or organism, depending on the context.

[0040] An “expression vector” is a nucleic acid construct, generated recombinantly or synthetically, with a series of specified nucleic acid elements that permit transcription of a particular nucleic acid. Typically, the expression vector includes a nucleic acid to be transcribed operably linked to a promoter.

[0041] “Fusion protein or polypeptide” refers to a polypeptide chain synthesized from a nucleic acid, where the nucleic acid comprises an open reading frame encoding two or more polypeptide or peptide sequences, where the two or more nucleic acid sequences generally do not occur together to encode a single open reading frame. One or all of the nucleic acids encoding the fusion protein may be of synthetic origin. The fusion protein may be synthesized by recombinant or synthetic means, or it may occur naturally.

[0042] “Gene expression” refers to transcription or translation, depending on the context. In transcription, mRNA is expressed from a gene. In translation, a polypeptide is expressed from mRNA.

[0043] An “immunoassay” is an assay that uses an antibody or antibody fragment to specifically bind an antigen. The immunoassay is characterized by the use of specific binding properties of a particular antibody to isolate, target, or quantify the antigen.

[0044] “Inhibitors” or “antagonists” and “activators” or “agonists” refer to inhibitory or activating molecules, respectively, identified using in vitro or in vivo assays, e.g., for the activation of a ligand, a receptor, a cofactor, or a gene. A “modulator” of gene activation or of protein activity is a molecule that is an inhibitor or an activator of a given gene or protein. The modulator may act alone, or it may use or require a cofactor, e.g., a protein, metal ion, or small molecule. Inhibitors are compounds that decrease, block, prevent, delay activation, inactivate, desensitize, or down regulate a gene or protein. Activators are compounds that increase, activate, facilitate, enhance activation, sensitize, or up regulate a gene or protein. To examine the extent of inhibition, samples or assays comprising a given gene or protein are treated with a potential activator or inhibitor and are compared to control samples without the inhibitor. Control samples (untreated with inhibitors) are assigned a relative activity value of 100%. Inhibition is achieved when the activity value relative to the control is about 90%, generally at least 85%, more generally at least 80%, preferably 75%, more preferably 70%, often 65%, more often 60%, typically 55%, more typically 50%, ordinarily 45%, ordinarily at least 40%, usually 35%, most usually 30%, most usually at least 25%, and most preferably less than 25%. Activation is achieved when the activity value relative to the control is about 110%, generally 120%, more generally 140%, more generally at least 160%, preferably 180%, more preferably 2-fold, often 2.5-fold, more often 5-fold, typically 10-fold, more typically 20-fold, usually 40-fold, and most usually over 40-fold higher. An “agonist” is a compound that interacts with a target or that can cause an increase in the activation of the target. An “antagonist” is a compound that opposes the actions of an agonist. An agonist prevents, inhibits, or neutralizes the activity of an agonist.

[0045] A composition that is “labeled” is detectable, either directly or indirectly, by spectroscopic, photochemical, biochemical, immunochemical, isotopic, or chemical means. For example, useful labels include ³²P, ³³P, ³⁵S, ¹⁴C, ³H, 1251, stable isotopes, fluorescent dyes, fluorettes (Rozinov and Nolan (1998) Chem. Biol. 5:713-728), electron-dense reagents, enzymes and/or substrates, e.g., as used in enzyme-linked immunoassays as with those using alkaline phosphatase or horse radish peroxidase. The label or detectable moiety is typically bound, either covalently, through a linker or chemical bound, or through ionic, van der Waals or hydrogen bonds to the molecule to be detected. “Radiolabeled” refers to a compound to which a radioisotope has been attached through covalent or non-covalent means. A “fluorophore” is a compound or moiety that absorbs light energy of one wavelength and emits light energy of a second, longer wavelength.

[0046] “Ligand” refers to an entity that specifically binds to a polypeptide or a complex of more than one polypeptide. A “ligand binding domain” is a region of a polypeptide that is able to bind to the entity. A ligand may be a soluble protein, a membrane-associated protein, or an integral membrane-bound protein. Where a ligand binds to a receptor, the question of which molecule is the ligand and which molecule is the receptor may be determined on a case-by-case basis. Generally, where the binding event results in cell signaling, a molecule that is constitutively bound to the cell that responds to the signal may be considered to be part of the receptor, and not part of the ligand. A freely diffusable and water-soluble entity that is involved in ligand/receptor interactions is usually a ligand, not a receptor. Ligands may also comprise oligosaccharides, lipids, and the like.

[0047] “Nucleic acid” refers to deoxyribonucleotides or ribonucleotides and polymers thereof, including single stranded and double stranded forms. The term encompasses nucleic acids containing nucleotide analogs or modified backbone residues or linkages. Examples of such analogs, e.g., phosphorothioates, phosphoramidates, and peptide-nucleic acids (PNAs).

[0048] A particular nucleic acid sequence also implicitly encompasses degenerate codon substitutions, i.e., different codons that code for the same amino acid, nucleotide base substitutions that code for conservative amino acid changes, and complementary sequences. The term nucleic acid may be used to refer, e.g., to a gene, cDNA, mRNA, oligonucleotide, and polynucleotide. A particular nucleic acid sequence also implicitly encompasses allelic variant, splice variants, and genetic mutations.

[0049] Substantial homology in the nucleic acid sequence comparison context means either that the segments, or their complementary strands, when compared, are identical when optimally aligned, with appropriate nucleotide insertions or deletions, in at least about 50% of the nucleotides, generally at least about 58%, ordinarily at least about 65%, often at least about 71%, typically at least about 77%, usually at least about 85%, preferably at least about 95 to 98% or more, and in particular embodiments, as high as about 99% or more of the nucleotides. Typically, selective hybridization will occur when there is at least about 55% homology over a stretch of at least about 30 nucleotides, preferably at least about 75% over a stretch of about 25 nucleotides, and most preferably at least about 90% over about 20 nucleotides. See, Kanehisa (1984) Nuc. Acids Res. 12:203-213. The length of homology comparison, as described, may be over longer stretches, and in certain embodiments will be over a stretch of at least about 17 nucleotides, usually at least about 28 nucleotides, typically at least about 40 nucleotides, and preferably at least about 75 to 100 or more nucleotides.

[0050] “Peptide” refers to a short sequence of amino acids, where the amino acids are connected to each other by peptide bonds. A peptide may occur free or bound to another moiety, such as a macromolecule or a polypeptide. Where a peptide is incorporated into a polypeptide chain, the term “peptide” may still be used to refer specifically to the short sequence of amino acids. A “peptide” may be connected to another moiety by way of a peptide bond, or by way of another type of linkage. A peptide is at least two amino acids in length. A peptide is usually less than about 25 amino acids in length, where the maximal length is a function of custom or context. The terms “peptide” and “oligopeptide” may be used interchangeably.

[0051] The term “protein” generally refers to the sequence of amino acids comprising a polypeptide chain. Protein may also refer to a three dimensional structure of the polypeptide. “Denatured protein” refers to a partially or totally denatured polypeptide, having some residual three dimensional structure or, alternatively, an essentially random three dimensional structure. The invention also encompasses polypeptide variants, e.g., involving glycosylation, phosphorylation, sulfation, disulfide bond formation, deamidation, isomerization, cleavage points in signal or leader sequence processing, covalent and non-covalently bound cofactors, and the like. The formation of disulfide linked proteins and variations thereof is described, e.g., see Woycechowsky and Raines (2000) Curr. Opin. Chem. Biol. 4:533-539; Creighton, et al. (1995) Trends Biotechnol. 13:18-23.

[0052] By “purified” and “isolated” is meant, when referring to a polypeptide, that the polypeptide is present in the substantial absence of the other biological macromolecules. The term “purified” as used herein means typically about 70%, more typically 75%, at least 80%, ordinarily 85%, more ordinarily 90%, preferably 95%, more preferably 98% by weight, or greater, of biological macromolecules present. The weights of water, buffers, salts, detergents, reductants, protease inhibitors, stabilizers, excipients, and other small molecules, especially those having a molecular weight of less than 1000, are generally not used in the determination of polypeptide purity (U.S. Pat. No. 6,090,611). Purity and homogeneity are typically determined using methods well known in the art (Scopes (1994) Protein Purification: Principles and Practice, Springer-Verlag, NY, N.Y.; Cunico, Gooding, and Wehr (1998) Basic HPLC and CE of Biomolecules, Bay Biological Laboratory, Inc. Hercules, Calif.).

[0053] “Recombinant” when used with reference, e.g., to a nucleic acid, cell, virus, plasmid, vector, or the like, indicates that these have been modified by the introduction of an exogenous, non-native nucleic acid or the alteration of a native nucleic acid, or have been derived from a recombinant nucleic acid, cell, virus, plasmid, or vector. Recombinant protein refers to a protein derived from a recombinant nucleic acid, virus, plasmid, vector, or the like.

[0054] “Soluble receptor” refers to receptors that are water-soluble and occur, e.g., in extracellular fluids, intracellular fluids, or weakly associated with a membrane. Soluble receptor also refers to receptors that are released from tight association with a membrane, e.g., by limited cleavage. Soluble receptor further refers to receptors that are engineered to be water soluble. See. e.g., Monahan, et al. (1997) J. Immunol. 159:4024-4034; Moreland, et al. (1997) New Engl. J. Med. 337:141-147; Borish, et al. (1999) Am. J. Respir. Crit. Care Med. 160:1816-1823; Uchibayashi, et al. (1989) J. Immunol. 142:3901-3908. The invention contemplates use of a soluble receptor to C1QSF3 for use in modulating the activity of C1QSF3, e.g., in the treatment of inflammation.

[0055] The phrase “specifically” or “selectively” binds, when referring to a ligand/receptor, antibody/antigen, or other binding pair, refers to a binding reaction which is determinative of the presence of the protein in a heterogeneous population of proteins and other biologics. Thus, under designated conditions, a specified ligand binds to a particular receptor and does not bind in a significant amount to other proteins present in the sample. The contemplated antibody of the invention binds to its antigen, or a variant or mutein thereof, with an affinity that is about ten times greater, more preferably 20-times greater, and still more preferably 100-times greater than the affinity with any other antibody. In a preferred embodiment the antibody will have an affinity which is greater than about 10⁹ liters/mol, as determined, for example, by Scatchard analysis (Munsen, et al. (1980) Analyt. Biochem. 107:220-239).

[0056] “Stringent conditions” are those that (1) employ low ionic strength and high temperature for washing, for example, 0.015 M sodium chloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50° C.; (2) employ during hybridization a denaturing agent, such as formamide, for example, 50% (vol/vol) formamide with 0.1% bovine serum albumin/0.1% Ficoll® (Sigma, St. Louis, Mo.)/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at 42° C.; (3) employ 50% formamide, 5×SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5× Denhardt's solution, sonicated salmon sperm DNA (50 ng/ml), 0.1% SDS, and 10% dextran sulfate at 42° C., with washes at 42° C. in 0.2× SSC and 0.1% SDS; or (4) employ a buffer of 10% dextran sulfate, 2× SSC (sodium chloride/sodium citrate), and 50% formamide at 55° C., followed by a high-stringency wash consisting of 0.1×SSC containing EDTA at 55° C. (U.S. Pat. No. 6,387,657 issued to Botstein, et al.). “Moderately stringent conditions” are described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), and include the use of a washing solution and hybridization conditions (e.g., temperature, ionic strength, and percent SDS) less stringent than described above.

[0057] “Treatment” refers to both therapeutic treatment and prophylactic or preventative measures.

[0058] II. General.

[0059] The present invention provides amino acid sequences and DNA sequences encoding mammalian C1QSF3, e.g., human C1QSF3 and murine C1QSF3. Human and murine C1QSF3 polynucleotide and polypeptide sequences are represented by SEQ ID NOs:9 and 10 (human) and SEQ ID NOs:11 and 12 (murine). Regions of homology between C1QSF3 and other members of the C1QSF family are shown (Table 1). Table 1 summarizes approximate residue boundaries of the structural motifs or characteristics of the C1QSF family of polypeptides. TABLE 1 SEQ ID Leader C1Q TNF C1Q/TNF Collagen C1QSF NO: sequence Domain Domain Domain Domains Human C1QSF1 2 284-420 Murine C1QSF1 4 273-409 Human C1QSF 2/5 6 1 to 16 188-323  83-187 Murine C1QSF 2/5 8 1 to 24 152-286  40-151 Human C1QSF3 10 1 to 20 908-952 1011-1047 Murine C1QSF3 12 1 to 18 50-95 Human C1QSF4 14 1 to 16  23-311 Murine C1QSF4 16 1 to 16  22-309 Human C1QSF6 18 1 to 15  97-234 36-95  Murine C1QSF6 20 1 to 15  97-234 36-95  Human C1QSF7 22 1 to 22 827-873 911-915 916-946 Murine C1QSF7 24 1 to 22 623-657 Human C1QSF8 26 768-819 878-917 713-767  Murine C1QSF8 28 652-703 758-796 602-651  Human C1QSF9 30 1 to 27 609-744 147-205; 208-266; 275-571. Murine C1QSF9 32 1 to 27 608-743 118-175; 185-243; 255-313; 316-374; 381-440; 444-503; 513-571. Human C1QSF11 34 1 to 32  71-205 Murine C1QSF11 36 1 to 40  79-213

[0060] Members of the C1q/TNF family appear to function, e.g., in collagen physiology, mammalian hibernation, adipose tissue physiology, neurogenesis, synapse formation, platelet physiology, skeletal physiology and growth plate formation, hormone-transport and binding, energy homeostasis and insulin response, elastin deposition, inflammation, adaptive immunity, and apoptosis. See, e.g., Kishore and Reid (2000) Immunopharmacology 49:159-170 and Doliana, et al. (2001) J. Biol. Chem. 276:12003-12011.

[0061] III. Analogs of C1QSF3 and Binding Compositions Thereto.

[0062] This invention also encompasses proteins or peptides having substantial amino acid sequence identity with the amino acid sequence of the C1QSF3, antigenic fragments thereof, and binding composition thereto, including polymorphic variants, allelic variants, and variants due to mutations and alternative splicing. The invention also contemplates C1QSF3 species that are modifed by recombinant or chemical techniques.

[0063] Mutagenesis can be conducted by making amino acid insertions or deletions. Substitutions, deletions, insertions, or any combinations may be generated to arrive at a final construct. Insertions include amino- or carboxy-terminal fusions. Random mutagenesis can be conducted at a target codon and the expressed mutants can then be screened for the desired activity. Methods for making substitution mutations at predetermined sites in DNA having a known sequence are well known in the art, e.g., by M13 primer mutagenesis or polymerase chain reaction (PCR) techniques.

[0064] Covalent derivatives can be prepared by linkage of functionalities to groups which are found in C1QSF amino acid side chains or at the N- or C-termini, e.g., by standard means. See, e.g., Lundblad and Noyes (1988) Chemical Reagents for Protein Modification, vols. 1-2, CRC Press, Inc., Boca Raton, Fla.; Hugli (ed.) (1989) Techniques in Protein Chemistry, Academic Press, San Diego, Calif.; and Wong (1991) Chemistry of Protein Conjugation and Cross Linking, CRC Press, Boca Raton, Fla.

[0065] Fusion polypeptides comprising C1QSF3, or a fragment thereof, as well as the nucleic acids encoding them, can be made by a number of methods (Sambrook, et al. (1989) Molecular Cloning: A Laboratory Manual (2d ed.), vols. 1-3, Cold Spring Harbor Laboratory; and Ausubel, et al. (eds.) (1993) Current Protocols in Molecular Biology, Greene and Wiley, NY). The contemplated fusion proteins include those containing an affinity tag, a reporter polypeptide or enzyme, a receptor-binding segment, a linker, an immune domain, or a cytokine or cytokine receptor. The contemplated embodiments include, e.g., luciferase, bacterial β-galactosidase, trpE, Protein A, β-lactamase, alpha amylase, alcohol dehydrogenase, yeast alpha mating factor, a FLAG sequence, and a His6 sequence. See, e.g., Godowski, et al. (1988) Science 241:812-816; Rais-Beghdadi, et al. (1998) Appl. Biochem. Biotechnol. 74:95-103; Dull, et al., U.S. Pat. No. 4,859,609). “Linkers” are generally short, self-complementary oligomers which connect longer nucleic acid sequences. Linkers may or may not maintain the open reading frame between the connected nucleic acid sequences, may or may not contain a restriction site, and may be blunt-ended or contain overhanging bases, depending on the use and context. See, e.g., Catalogue (2002) New England Biolabs, Inc., Beverly, Mass., pp. 142-143.

[0066] The invention contemplates C1QSF3 polypeptides modified by changes in oligosaccharide identity or content, and location of oligosaccharides on the polypeptide. See, e.g., Elbein (1987) Ann. Rev. Biochem. 56:497-534; Summers (1988) Bio/Technology 6:47:55; and Kaufman (1990) Meth. Enzymol. 185:487/511. Also embraced are versions of the peptides and polypeptides with the same primary amino acid sequence which have other minor modifications, including phosphorylated amino acid residues, e.g., phosphotyrosine, phosphoserine, or phosphothreonine. The invention also contemplates modification by a moiety comprising a lipid, e.g., phosphatidyl inositol (Low (1989) Biochim. Biophys. Acta 988:427-454; Tse, et al. (1985) Science 230:1003-1008; and Brunner, et al. (1991) J. Cell Biol. 114:1275-1283).

[0067] The invention further contemplates immobilization, e.g., to a bead, magnetic bead, slide, microarray, fabric, or device such as a lab-on-a-chip. The invention contemplates immobilized nucleic acids, polypeptides, peptides, antibodies and antibody fragments, as well as other reagents.

[0068] IV. Screening for C1QSF3 expression and for therapeutic agents.

[0069] Cells or animals may be screened for expression of a C1QSF3 gene. Levels of mRNA may be measured by techniques using hybridization, such as Northern blotting or the molecular beacon technique (Liu, et al. (2002) Analyt. Biochem. 300:40-45), or techniques that combine reverse transcription and the polymerase chain reaction (RT-PCR). See, e.g., Huang, et al. (2000) Cancer Res. 60:6868-6874). PCR product can be measured by incorporated radiolabel, or by electrophoresis followed by staining with a dye, such as ethidium bromide. Alternatively, PCR product can be measured during each cycle of the PCR reaction, e.g., by means of TaqMan® (PE Applied Biosystems, Foster City, Calif.) probes or by SYBR Green I® (Molecular Probes, Eugene, Oreg.) (Wittwer, et al. (1997) Biotechniques 22:130-138; Schmittgen, et al. (2000) Analyt. Biochem. 285:194-204). The TaqMan® technique, and similar techniques, rely on nuclease digestion of a probe, where digestion releases a fluorescing dye, where release results in an increase in fluorescence (Heid, et al. (1996) Genome Res. 6:989-994).

[0070] Microarrays of nucleic acids may be used for screening (Ausubel, et al. (2001) Curr. Protocols Mol. Biol., Vol. 4, John Wiley and Sons, New York, N.Y., pp. 22.0.1-22.3.26; Huang, et al. (2000) Cancer Res 60:6868-6874). Screening of cells and tissues is described (Ausubel, et al. (2001) Curr. Protocols Mol. Biol., Vol. 4, John Wiley and Sons, New York, N.Y., pp. 25.0.1-25B.2.20 and Ausubel, et al. (2001) Curr. Protocols Mol. Biol., Vol. 3, John Wiley and Sons, New York, N.Y., pp. 14.0.1-14.14.8).

[0071] Variations and hybrids of the above techniques may be used, i.e., antibodies bearing covalently linked DNA may be used as probes, where bound antibody is detected by the PCR method (Sims, et al. (2000) Analyt. Biochem. 281:230-232). The above techniques can also be used for screening of therapeutic agents that modulate the expression, processing, secretion, and binding functions of C1QSF3.

[0072] V. Protein Purification.

[0073] It is contemplated to purify the polypeptide diagnostics or therapeutics of the invention, such as antigens, antibodies, and antibody fragments, by methods that are established in the art.

[0074] Initial stages of purification may include homogenization of cells, i.e., by a sonicator, French press, or blender, and selective precipitation by fractionation with ammonium sulfate, polyethylene glycol, or solvents (Dennison and Lovrien (1997) Protein Expression Purif. 11:149-161). It is recognized that protein integrity during purification may be enhanced by including solvents such as glycerol or sucrose, reductants such as dithiothreitol (DTT), anti-protease “cocktails,” albumin supplements, reduced temperatures, and by genetic engineering of the protein itself (Murby, et al. (1996) Protein Expression Purif. 7:129-136). Contaminating proteases, or auto-proteolytic action, can cleave peptide bonds at all stages of purity of a protein, where any resulting change in function depends, e.g., on the position of cleavage and on the protein target.

[0075] Polypeptides may be purified by ion exchange chromatography, such as diethylaminoethylcellulose, phosphocellulose, and carboxymethylcellulose, or by molecule sieve chromatography, as with Sephadex® and Sephacryl® gel filtration media (Pharmacia catalogue (2001) Amersham Pharnacia Biotech, Inc., Piscataway, N.J.). Polypeptides may be purified by affinity chromatography, as with immobilized lectins, immobilized antibodies, immobilized ligands or substrates, and immobilized hydrophobic arms. Glycoprotein biochemistry and purification by lectins is described (Ausubel, et al. (2001) Curr. Protocols Mol. Biol., Vol. 3, John Wiley and Sons, New York, N.Y., pp. 17.0.1-17.23.8). Polypeptides may be engineered to contain a tag specially formulated to facilitate purification, expressed in a host cell, and then purified. Such tags include an oligohistidine tag (Rajan, et al. (1998) Protein Expression Purif. 13:67-72), glutathione S-transferase, streptavidin, or protein A, for example (Pharmacia catalogue (2001) Amersham Pharmacia Biotech, Inc., pp. 543-567, 605-654). The immobilized ligands for these tags are nickel, glutathione, biotin, and Fc fragment, respectively. Machine-based methods of protein purification include preparative isoelectric focusing, preparative polyacrylamide gel electrophoresis, two dimensional electrophoretic gels, and systems operating under elevated pressure, such as high pressure liquid chromatography (HPLC) (Gooding and Regnier (2002) HPLC of Biological Molecules, 2^(nd) ed., Marcel Dekker, NY; Cunico, Gooding, and Wehr (1998) Basic HPLC and CE of Biomolecules, Bay Biological Laboratory, Inc. Hercules, Calif.). Instruments such as the BioCAD® (Applied Biosystems, Foster City, Calif.) allow the automated generation of pH gradients, salt and buffer gradients, and flow rates during protein purification, thus facilitating the determination of a workable purification protocol.

[0076] Membrane-bound proteins may require a different type of detergent at the various steps in a purification procedure. Different types of detergent may be required for initial solubilization, for maintenance of solubility during chromatographic purification, and during assay of biological or antigenic activity. For initial solubilization, ionic detergents such as sodium cholate, or non-ionic detergents such as 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) or Triton X-100®, may be suitable. However, zwitterionic detergents, such as CHAPS, or non-ionic detergents, such as Triton X-100, may be required during fractionation on an ion exchange column. Where the protein is to be maintained in a non-denatured, biologically active state, the detergent may be Triton X-100, Tween 20, Brij 58, CHAPS, cholate, deoxycholate, or other detergents or stabilizers, as described, see, e.g., Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, N.Y. and Sigma catalogue (2002) Sigma-Aldrich, Co., St. Louis, Mo.

[0077] VI. Antibodies.

[0078] Antibodies can be raised to various embodiments of C1QSF3, including species, polymorphic, allelic, and mutational variants, and fragments thereof, both in their naturally occurring forms and in their recombinant forms. Additionally, antibodies can be raised to C1QSF3 in either their active forms or in their inactive forms, including native or denatured versions. Anti-idiotypic antibodies are also contemplated.

[0079] Antibodies, including humanized antibodies, monoclonal antibodies, and binding fragments, such as Fab, F(ab)₂, and Fv fragments are contemplated. Antibodies may be agonistic or antagonistic, by binding to a protein, e.g., a ligand or a receptor, and inhibiting or stimulating the binding of that protein to its receptor. Antibodies that simultaneously bind to a ligand and receptor are contemplated. Monoclonal antibodies will usually bind with at least a K_(D) of about 1 mM, more usually at least about 300 μM, typically at least about 100 μM, more typically at least about 30 μM, preferably at least about 10 μM, and more preferably at least about 3 μM or better.

[0080] While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo either chemically or by using recombinant DNA methodology. Thus, the term antibody, as used herein, also includes antibody fragments produced by the modification of whole antibodies, or those synthesized de novo using recombinant DNA methodologies, such as recombinant IgG antibodies (U.S. Pat. No. 4,816,567 issued to Cabilly, et al; U.S. Pat. No. 4,642,334 issued to Moore, et al.; Queen, et al. (1989) Proc. Natl Acad. Sci. USA 86:10029-10033), single chain antibodies, or antibodies acquired by phage display, and monoclonal antibodies made by the hybridoma method (Kohler, et al. (1975) Nature 256:495-497).

[0081] For preparation of monoclonal or polyclonal antibodies, any technique known in the art can be used (see, e.g., Kozbor, et al. (1983) Immunology Today 4:72; Cole, et al. (1985) in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., New York, N.Y., pp. 77-96). Monoclonal antibodies are generally derived from non-human sources, rather than from human sources (Harlow and Lane (1988) Antibodies A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., pp. 139-243).

[0082] The use of non-human sources can limit the therapeutic efficiency of a monoclonal antibody. Antibodies derived from non-human sources can provoke an immune response, weak recruitment of effector function, and rapid clearance from the bloodstream (Baca, et al. (1997) J. Biol. Chem. 272:10678-10684). For these reasons, it may be desired to prepare therapeutic antibodies by humanization (Carpenter, et al. (2000) J. Immunol. 165:6205; He, et al. (1998) J. Immunol. 160:1029; Tang, et al. (1999) J. Biol. Chem. 274:27371-27378). A humanized antibody contains the amino acid sequences from six complementarity determining regions (CDRs) of the parent mouse antibody, which are grafted on a human antibody framework. To achieve optimal binding, the humanized antibody may need fine-tuning, by changing certain framework amino acids, usually involved in supporting the conformation of the CDRs, back to the corresponding amino acid found in the parent mouse antibody.

[0083] An alternative to humanization is to use human antibody libraries displayed on phage (Vaughan, et al. (1996) Nat. Biotechnol. 14:309-314; Barbas (1995) Nature Med. 1:837-839; de Haard, et al. (1999) J. Biol. Chem. 274:18218-18230; McCafferty et al. (1990) Nature 348:552-554; Clackson et al. (1991) Nature 352:624-628; Marks et al. (1991) J. Mol. Biol. 222:581-597), or human antibody libraries contained in transgenic mice (Mendez, et al. (1997) Nature Genet. 15:146-156). The phage display technique can be used for screening for and selecting antibodies with high binding affinity (Hoogenboom and Chames (2000) Immunol. Today 21:371-377; Barbas, et al. (2001) Phage Display: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Kay, et al. (1996) Phage Display of Peptides and Proteins: A Laboratory Manual, Academic Press, San Diego, Calif.). Use of the phage display method can provide a DNA sequence that provides a tight binding monovalent antibody, as displayed on the surface of filamentous phage. With this DNA sequence in hand, the researcher can build a tight binding humanized bivalent antibody. A phage display library may comprise single chain antibodies where heavy and light chain variable regions are fused by a linker in a single gene, or it may comprise co-expressed heavy and light chains (de Bruin, et al. (1999) Nat. Biotechnol. 17:397-399).

[0084] Single chain antibodies are described, e.g., in Malecki, et al. (2002) Proc. Natl. Acad. Sci. USA 99:213-218 and U.S. Pat. No. 4,946,778 issued to Ladner, et al., while single domain antibodies are described by Conrath, et al. (2001) J. Biol. Chem. 276:7346-7350 and Desmyter, et al. (2001) J. Biol. Chem. 276:26285-26290). Bispecific antibodies are described. See, e.g., U.S. Pat. Nos. 5,932,448 issued to Tso, et al., 5,532,210 issued to Paulus, and 6,129,914 issued to Weiner, et al. Bispecific antibodies may be synthesized using leucine zipper technology (Kostelney, et al. (1992) J. Immunol. 148:1547-1553; U.S. Pat. No. 6,133,426 issued to Gonzalez, et al.).

[0085] Purification of antigen is not necessary for the generation of antibodies. Immunization can be performed by DNA vector immunization. See, e.g., Wang, et al. (1997) Virology 228:278-284. Alternatively, animals can be immunized with cells bearing the antigen of interest. Splenocytes can then be isolated from the immunized animals, and the splenocytes can fused with a myeloma cell line to produce a hybridoma (Meyaard, et al. (1997) Immunity 7:283-290; Wright, et al. (2000) Immunity 13:233-242; Preston, et al. (1997) Eur. J. Immunol. 27:1911-1918). Resultant hybridomas can be screened for production of the desired antibody by means of functional assays or biological assays, that is, assays not dependent on possession of the purified antigen. Immunization with cells may prove superior for antibody generation than immunization with purified antigen (Kaithamana, et al. (1999) J. Immunol. 163:5157-5164).

[0086] Antigen fragments may be joined to other materials, such as fused or covalently joined polypeptides, to be used as immunogens. An antigen and its fragments may be fused or covalently linked to a variety of immunogens, such as keyhole limpet hemocyanin, bovine serum albumin, or ovalbumin (Coligan, et al. (1994) Current Protocols in Immunol., Vol. 2, Unit 9.3-9.4, John Wiley and Sons, New York, N.Y.). Peptides of suitable antigenicity can be selected from the polypeptide target, using an algorithm, such as those of Parker, et al. (1986) Biochemistry 25:5425-5432; Jameson and Wolf (1988) Cabios 4:181-186; or Hopp and Woods (1983) Mol. Immunol. 20:483-489.

[0087] The signal sequence or leader sequence can be predicted (Menne, et al. (2000) Bioinformatics Applications Note 16:741-742; Wren, et al. (2002) Comput. Methods Programs Biomed. 68:177-181; von Heijne (1983) Eur. J. Biochem. 133:17-21; von Heijne (1986) Nucleic Acids Res. 14:4683-4690).

[0088] Antibody to antigen binding properties can be measured, e.g., by surface plasmon resonance (Karlsson, et al. (1991) J. Immunol. Methods 145:229-240; Neri, et al. (1997) Nat. Biotechnol. 15:1271-1275; Jonsson, et al. (1991) Biotechniques 11:620-627) orby competition ELISA (Friguet, et al. (1985) J. Immunol. Methods 77:305-319; Hubble (1997) Immunol. Today 18:305-306).

[0089] A variety of approaches are used to make therapeutic antibodies, or fragments thereof. See, e.g., (Yip and Ward (2002) Cancer Immunol. Immunother. 50:569-587; U.S. Pat. No. 5,772,997 issued to Hudziak, et al.; Lin and Castro (1998) Curr. Opinion Chem. Biol. 2:453-457; Rader, et al. (1998) Proc. Natl. Acad. Sci. USA 95:8910-8915; Targan, et al. (1997) New Engl. J. Med. 337:1029; Joosten, et al. (1996) Arthritis and Rheumatism 39:797).

[0090] Therapeutic antibodies occurring as conjugated antibodies or fusion protein antibodies are described. Antibodies may be conjugated to toxins (van Oosterhout, et al. (2001) Int. J. Pharm. 221:175-186; Marsh and Klinman (1990) J. Immunol. 144:1046-1051; Kreitman (2001) Curr. Pharm. Biotechnol. 2:313-325; Dinndorf, et al. (2001) J. Immunother. 24:511-516), small drug molecules (Wahl, et al. (2001) Int. J. Cancer 93:540-600; Garber (2000) J. Nat. Cancer Instit. 92:1462-1464; Everts, et al. (2002) J. Immunol. 168:883-889), enzymes for generating an active drug from a pro-drug (Chen, et al. (2001) Int. J. Cancer 94:850-858), to liposomes (Shaik, et al. (2001) J. Control. Release 76:285-295; Park, et al. (2001) J. Control. Release 74:95-113), polyethylene glycol (PEG) (Solorzano, et al. (1998) J. Appl. Physiol. 84:1119-1130; Rosenberg, et al. (2001) J. Appl. Physiol. 91:2213-2223; Bendele, et al. (2000) Arthritis Rheum. 43:2648-2659; Trakas and Tzartos (2001) J. Neurochem. 120:42-49; Chapman, et al. (1999) Nat. Biotechnol. 17:780-783), and recognition tags (Gaidamakova, et al. (2001) J. Control. Release 74:341-347).

[0091] Conjugated antibodies are useful for diagnostic or kit purposes, and include antibodies coupled to dyes, such as fluorescein or phycoerythrin, radioactive atoms, such as iodine-125, enzymes, such as horse radish peroxidase (Le Doussal, et al. (1991) J. Immunol. 146:169-175; Gibellini, et al. (1998) 160:3891-3898; Hsing and Bishop (1999) J. Immunol. 162:2804-2811), colloidal gold (Everts, et al. (2002) J. Immunol. 168:883-889), or various other moieties (Harlow and Lane (1988) supra). The binding of diagnostic antibodies to cells can be measured by immunochemistry or by flow cytometry (Everts, et al. (2002) J. Immunol. 168:883-889). See also, Chan (1987) Immunology: A Practical Guide, Academic Press, Orlando, Fla.; Price and Newman (1991) Principles and Practice of Immunoassay, Stockton Press, N.Y.; and Ngo (1988) Nonisotopic Immunoassay, Plenum Press, N.Y.

[0092] The antibodies of this invention can also be used for affinity chromatography in isolating the antibody's target antigen or related proteins. Columns can be prepared where the antibodies are linked to a solid support. See, e.g., Wilchek, et al. (1984) Meth. Enzymol. 104:3-55.

[0093] Antibodies to C1QSF3 having substantially the same nucleic acid and amino acid sequence as those recited herein, but possessing substitutions that do not substantially affect the functional aspects of the nucleic acid or amino acid sequence, are within the definition of the contemplated invention. Variants with truncations or deletions of regions which do not change the biological functions of these nucleic acids and polypeptides are also within the definition of the contemplated invention.

[0094] VII. Therapeutic Compositions.

[0095] Formulations of antibodies, binding composition, polypeptides, or small molecule therapeutics are prepared for storage by mixing with physiologically acceptable carriers, excipients, or stabilizers in the form of, e.g., lyophilized powders, slurries, aqueous solutions. See, e.g., Hardman, et al. (2001) Goodman and Gilman's the Pharmacological Basis of Therapeutics, McGraw-Hill, New York, N.Y.; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, N.Y.; Avis, et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; and Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems Dekker, N.Y.

[0096] Carriers, excipients, detergents, surfactants, and stabilizers are described, see, e.g., Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, N.Y.; Sigma Catalogue (2002) Sigma-Aldrich, Co., St. Louis, Mo.; U.S. Pat. No. 6,096,728 issued to Collins, et al.; U.S. Pat. No. 6,342,220 issued to Adams, et al.; U.S. Pat. No. 5,440,021 issued to Chuntharapai, et al.

[0097] The antibody, binding composition, polypeptide, or small molecule to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes, prior to or following lyophilization and reconstitution. The antibody ordinarily will be stored in lyophilized form or in solution.

[0098] Therapeutic compositions comprising an antibody or small molecule can be administered, e.g., by systemic, intraperitoneal, intramuscular, and intratumor routes. Sustained-release preparations (Sidman et al. (1983) Biopolymers, 22:547-556; Langer et al. (1981) J. Biomed. Mater. Res. 15:167-277; Langer (1982) Chem. Tech. 12:98-105; U.S. Pat. Nos. 6,387,404; 6,375,972), liposomes (Epstein et al. (1985) Proc. Natl. Acad. Sci. USA, 82:3688-3692; Hwang et al. (1980) Proc. Natl. Acad. Sci. USA, 77:4030-4034; U.S. Pat. Nos. 6,387,397; 6,379,699; 6,372,720; 6,348,214; 6,290,987; 6,372,259; 6,335,035; 6,328,979; 6,312,728), or aerosols may be used to supply the therapeutic composition. Adenovirus and other vectors are also contemplated as a delivery agent for the contemplated invention (See, e.g., U.S. Pat. Nos. 6,387,368; 6,379,943; 6,297,220; 6,281,010; and 6,245,966).

[0099] An “effective amount” of antibody or other therapeutic to be employed will depend, for example, upon the therapeutic objectives, the route of administration, the type of antibody employed, and the condition of the patient. Accordingly, it will be necessary for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect. Typically, the clinician will administer the antibody until a dosage is reached that achieves the desired effect. The progress of this therapy is easily monitored by conventional assays.

[0100] In the treatment and prevention of an inflammatory disorder the therapeutic composition will be formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the antibody, the particular type of antibody, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The “therapeutically effective amount” of antibody to be administered will be governed by such considerations, and is the minimum amount necessary to prevent, ameliorate, or treat the proliferative disorder. Such amount is preferably below the amount that is toxic to the host.

[0101] As a general proposition, the initial pharmaceutically effective amount of the antibody administered parenterally will be in the range of about 0.1 to 50 mg/kg of patient body weight per day, with the typical initial range of antibody used being 0.3 to 20 mg/kg/day, more preferably 0.3 to 15 mg/kg/day. The desired dosage can be delivered by a single bolus administration, by multiple bolus administrations, or by continuous infusion administration of antibody, depending on the pattern of pharmacokinetic decay that the practitioner wishes to achieve.

[0102] The therapeutic may be formulated with one or more agents currently used to prevent or treat an immune condition, autoimmune condition, or inflammatory condition.

[0103] VIII. Kits.

[0104] This invention also contemplates use of C1QSF3 proteins and fragments thereof, nucleic acids, and fragments thereof, such as primers and probes, in a diagnostic kit. The invention also contemplates use of binding composition, including antibodies or antibody fragments, for the detection or quantitation of C1QSF3 proteins, C1QSF3, and breakdown products. Typically, the kit will have a compartment containing either a C1QSF3 polypeptide, nucleic acid coding for part or all of a C1QSF3, or a reagent that recognizes the polypeptide or polypeptide fragment, e.g., an antibody or receptor fragment. The invention also contemplates nucleic acids, nucleic acid fragments, or nucleic acid probes or primers.

[0105] For example, a kit for determining the binding of a test compound, e.g., acquired from a biological sample or from a chemical library, would typically comprise a control compound, a labeled compound, and a means for separating free labeled compound from bound labeled compound. The means for separating free labeled from bound labeled compound may be a solid phase matrix containing an antibody that binds the test compound and the labeled compound. Diagnostic assays can be used with biological matrices such as live cells, lysates, fixed cells, cell cultures, bodily fluids, forensic samples. Various commercial assays exist, such as radioimmunoassays (RIA), enzyme-linked immunoassay (ELISA), substrate-labeled fluorescent immunoassay, and the like.

[0106] Numerous methods exist for the separation of bound ligand from free ligand, or bound test compound from free test compound. Methods of immobilizing ligands or test compounds include, without limitation, direct adhesion to plastic, use of a capture antibody, chemical coupling, biotin-avidin couplings, and biotin-streptavidin couplings. Another approach for the separation of bound from free test compounds is to use an organic solvent to lake advantage of differences in relative solubility, or a precipitant such as polyethylene glycol (PEG), ammonium sulfate, or other salt.

[0107] IX. Uses.

[0108] The present invention provides reagents which will find use in diagnostic and therapeutic applications, e.g., relating to the modulation of the activity, behavior, and development of cells, including monocytes, mast cells, dendritic cells, macrophages, lymphocytes, NK cells, hematopoietic precursors, neutrophils, and epithelial cells. The reagents will also find use in applications relating to the development or physiology of various tissues and organs, e.g., epithelial tissues, endothelial tissues, lungs, heart, skin, small and large intestines, joints, thyroid, spinal cord, and the central nervous system.

[0109] The present invention provides C1QSF3, isolated fragments of C1QSF3, analogs or muteins thereof, and binding compositions specific for C1QSF3, or a derivative or fragment thereof, for use in the treatment of conditions associated with abnormal physiology or development, e.g., relating to the heart, lungs, gut, joints, and cells of the immune system. The C1QSF3, binding composition thereto, and fragments and analogues thereof, are expected to be of use for the treatment of pathological conditions, e.g., inflammation, infection, abnormal proliferation, cancer, metastasis, or pathological cell adhesion. The invention is expected to be of use for the diagnosis or treatment of psoriasis, Hashimoto's thyroiditis, asthma, or inflammatory bowel disease, e.g., Crohn's disease.

[0110] For example, a disease condition associated with abnormal expression or abnormal signaling by C1QSF3 should be a likely target for an agonist or antagonist of an antigen of C1QSF3. Thus, C1QSF3 will likely modulate interactions of cells of the lung, skin, or joint with other cell types, e.g., cells which possess a receptor therefor. These interactions would lead, in particular contexts, to modulation of cell growth, cytokine synthesis by those or other cells, or development of particular effector cells.

[0111] Many modifications and variations of this invention can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. The specific embodiments described herein are offered by way of example only, and the invention is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled.

EXAMPLES

[0112] I. General Methods.

[0113] Some of the standard methods are described or referenced, e.g., in Maniatis, et al. (1982) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor Press; Sambrook and Russell (2001) Molecular Cloning, 3^(rd.) ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Wu (1993) Recombinant DNA, Vol. 217, Academic Press, San Diego, Calif.; Innis, et al. (eds.) (1990) PCR Protocols: A Guide to Methods and Applications, Academic Press, N.Y. Standard methods are also found in Ausbel, et al. (2001) Current Protocols in Molecular Biology, Vols. 1-4, John Wiley and Sons, Inc. New York, N.Y., which describes cloning in bacterial cells and DNA mutagenesis (Vol. 1), cloning in mammalian cells and yeast (Vol. 2), glycoconjugates and protein expression (Vol. 3), and bioinformatics (Vol. 4). Methods for producing transgenic animals are described, e.g., in Jackson and Abbott (eds.) (2000) Mouse Genetics and Transgenics, Oxford Univ. Press, Oxford, UK; Hofker, et al. (eds.) (2002) Transgenic Mouse Methods and Protocols, Humana Press, Clifton, N.J.

[0114] Methods for protein purification such as ammonium sulfate fractionation, column chromatography, electrophoresis, isoelectric focusing, centrifugation, and crystallization, are described (Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 1, John Wiley and Sons, Inc., New York). Chemical analysis, chemical modification, post-translational modification, and glycosylation of proteins is described. See, e.g., Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 2, John Wiley and Sons, Inc., New York; Walker (ed) (2002) Protein Protocols Handbook, Humana Press, Towota, N.J.; Lundblad (1995) Techniques in Protein Modification, CRC Press, Boca Raton, Fla. The production, purification, and fragmentation of polyclonal and monoclonal antibodies is described (Coligan, et al. (2001) Current Protcols in Immunology, Vol. 1, John Wiley and Sons, Inc., New York; Harlow and Lane (1999) Using Antibodies, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.); Harlow and Lane (1988) supra).

[0115] Standard techniques for characterizing ligand/receptor interactions are described (Coligan, et al. (2001) Current Protcols in Immunology, Vol. 4, John Wiley and Sons, Inc., New York).

[0116] Cell culture techniques are described in Doyle, et al. (eds.) (1994) Cell and Tissue Culture: Laboratory Procedures, John Wiley and Sons, NY. FACS analysis is described in Melamed, et al. (1990) Flow Cytometry and Sorting Wiley-Liss, Inc., New York, N.Y.; Shapiro (1988) Practical Flow Cytometry Liss, New York, N.Y.; and Robinson, et al. (1993) Handbook of Flow Cytometry Methods Wiley-Liss, New York, N.Y.

[0117] Reagents for fluorescent labeling of proteins, nucleic acids, lipids, carbohydrates, and cells are from Molecular Probes, Inc. (Eugene, Oreg.). These reagents include those that modify thiols, amines, hydroxylated molecules, fluorescent biotin derivatives, and photoreactive reagents.

[0118] II. Identification of Human C1QSF.

[0119] A structure-guided alignment for the TNF family was constructed and an HMM (Hidden Markov model) was built from the HMM. The HMM was used to in an hframe search versus the Schering human contigs. Hframe is an algorithm that allows you to search a nucleotide database with a protein HMM. The sequences from the hframe run were compared by blast to a set of known TNF and C1Q sequences. Sequences that were not known, i.e., sequences that shared less than 95% homology to a known protein, were investigated further. C1QSF1-5 (human) were identified from the output of this search. Mouse sequences where identified by Blasting the human sequences vs. the mouse EST database. C1QSF6-11 human and mouse sequences were identified by blasting C1QSF1-5 against human and mouse EST and protein databases. Clones were obtained for these genes, and their sequences were confirmed.

[0120] III. Cellular Expression of Mammalian C1QSF3.

[0121] Tissue and cell distribution of C1QSF expression was determined by TaqMan® analysis (PE Applied Biosystems, Foster City, Calif.). Expression from human and murine cells and tissues is shown (Table 2). TABLE 2 Expression ot C1QSF3 in cells and tissues. (−) Means little or no detectable expression. Skin control (human) + Skin psoriasis (human) +++ Colon control (human) + Colon Crohn's (human) +++ Thyroid control (human) ++ Thyroid Hashimoto's thyroiditis (human) +++++ Lung control (human) ++++++ Lung idiopathic pulmonary fibrosis (human) ++++++++ Lung hypersensitivity pneumonitis (human) +++++++ Heart fetal (human) ++++++++ Small intestines fetal (human) ++ Hematopoietic precursor, activated (human) ++++++ Premonocyte resting (human) ++ Monocyte activated with lipopolysaccharide (LPS) (human) +++ T cell TH1 resting (human) − T cell TH2 resting (human) − Epithelial cell bronchial (human) − Spleen C57BL/6, untreated (murine) − Spleem C57BL/6, TNFα knockout, untreated (murine) +++++ Lung BALB/c untreated (murine) + Lung asthma model OVA challenged (murine) ++++ Lung tolerized OVA challenged (murine) + Lung infected Nippostrongulus (murine) +

[0122] IV. Preparation of Antibodies that Bind C1QSF3.

[0123] Analysis of human C1QSF3 (SEQ ID NO:10) for antigenicity using a Welling plot (Vector NTI® Suite V.7, InforMax®, Bethesda, Md.) revealed a number of regions of increased antigenicity. These regions approximately include amino acid residues 100-240, 280-295, 590-610, 770-810, and 970-120.

[0124] Many modifications and variations of this invention, as will be apparent to one of ordinary skill in the art can be made to adapt to a particular situation, material, composition of matter, process, process step or steps, to preserve the objective, spirit, and scope of the invention. All such modifications are intended to be within the scope of the claims appended hereto without departing from the spirit and scope of the invention. The specific embodiments described herein are offered by way of example only, and the invention is to be limited by the terms of the appended claims, along with the full scope of the equivalents to which such claims are entitled; and the invention is not to be limited by the specific embodiments that have been presented herein by way of example.

DESCRIPTION OF SEQUENCE IDENTIFICATION NUMBERS

[0125] SEQ ID NO: 1 is human C1QSF1 nucleic acid sequence

[0126] SEQ ID NO: 2 is human C1QSF1 polypeptide sequence

[0127] SEQ ID NO: 3 is murine C1QSF1 nucleic acid sequence

[0128] SEQ ID NO: 4 is murine C1QSF1 polypeptide sequence

[0129] SEQ ID NO: 5 is human C1QSF2/5 nucleic acid sequence

[0130] SEQ ID NO: 6 is human C1QSF2/5 polypeptide sequence

[0131] SEQ ID NO: 7 is murine C1QSF2/5 nucleic acid sequence

[0132] SEQ ID NO: 8 is murine C1QSF 2/5 polypeptide sequence

[0133] SEQ ID NO: 9 is human C1QSF3 nucleic acid sequence

[0134] SEQ ID NO: 10 is human C1QSF3 polypeptide sequence

[0135] SEQ ID NO: 11 is murine C1QSF3 nucleic acid sequence

[0136] SEQ ID NO: 12 is murine C1QSF3 polypeptide sequence

[0137] SEQ ID NO: 13 is human C1QSF4 nucleic acid sequence

[0138] SEQ ID NO: 14 is human C1QSF4 polypeptide sequence

[0139] SEQ ID NO: 15 is murine C1QSF4 nucleic acid sequence

[0140] SEQ ID NO: 16 is murine C1QSF4 polypeptide sequence

[0141] SEQ ID NO: 17 is human C1QSF6 nucleic acid sequence

[0142] SEQ ID NO: 18 is human C1QSF6 polypeptide sequence

[0143] SEQ ID NO: 19 is murine C1QSF6 nucleic acid sequence

[0144] SEQ ID NO: 20 is murine C1QSF6 polypeptide sequence

[0145] SEQ ID NO: 21 is human C1QSF7 nucleic acid sequence

[0146] SEQ ID NO: 22 is human C1QSF7 polypeptide sequence

[0147] SEQ ID NO: 23 is murine C1QSF7 nucleic acid sequence

[0148] SEQ ID NO: 24 is murine C1QSF7 polypeptide sequence

[0149] SEQ ID NO: 25 is human C1QSF8 nucleic acid sequence

[0150] SEQ ID NO: 26 is human C1QSF8 polypeptide sequence

[0151] SEQ ID NO: 27 is murine C1QSF8 nucleic acid sequence

[0152] SEQ ID NO: 28 is murine C1QSF8 polypeptide sequence

[0153] SEQ ID NO: 29 is human C1QSF9 nucleic acid sequence

[0154] SEQ ID NO: 30 is human C1QSF9 polypeptide sequence

[0155] SEQ ID NO: 31 is murine C1QSF9 nucleic acid sequence

[0156] SEQ ID NO: 32 is murine C1QSF9 polypeptide sequence

[0157] SEQ ID NO: 33 is human C1QSF11 nucleic acid sequence

[0158] SEQ ID NO: 34 is human C1QSF11 polypeptide sequence

[0159] SEQ ID NO: 35 is murine C1QSF11 nucleic acid sequence

[0160] SEQ ID NO: 36 is murine C1QSF11 polypeptide sequence

1 36 1 1263 DNA Homo sapiens 1 atgactcaga ttcaaggaac ttgtaacttt atgcaagagt ctgttcttga ctttgacaaa 60 ccttcaagtg caattccaac gtcacaaccg ccttcagcta ctccaggtag ccccgtagca 120 tctaaagaac aaaatctgtc cagtcaaagt gattttcttc aagagccgtt acaggtattt 180 aacgttaatg cacctctgcc tccacgaaaa gaacaagaaa taaaagaatc cccttattca 240 cctggctaca atcaaagttt taccacagca agtacacaaa caccacccca gtgccaactg 300 ccatctatac atgtagaaca aactgtccat tctcaagaga ctgcagcaaa ttatcatcct 360 gatggaacta ttcaagtaag caatggtagc cttgcctttt acccagcaca gacgaatgtg 420 tttcccagac ctactcagcc atttgtcaat agccggggat ctgttagagg atgtactcgt 480 ggtgggagat taataaccaa ttcctatcgg tcccctggtg gttataaagg ttttgatact 540 tatagaggac tcccttcaat ttccaatgga aattatagcc agctgcagtt ccaagctaga 600 gagtattctg gagcacctta ttcccaaagg gataatttcc agcagtgtta taagcgagga 660 gggacatctg gtggtccacg agcaaattcg agagcagggt ggagtgattc ttctcaggtg 720 agcagcccag aaagagacaa cgaaaccttt aacagtggtg actctggaca aggagactcc 780 cgtagcatga cccctgtgga tgtgccagtg acaaatccag cagccaccat actgccagta 840 cacgtctacc ctctgcctca gcagatgcga gttgccttct cagcagccag aacctctaat 900 ctggcccctg gaactttaga ccaacctatt gtgtttgatc ttcttctgaa caacttagga 960 gaaacttttg atcttcagct tggtagattt aattgcccag tgaatggcac ttacgttttc 1020 atttttcaca tgctaaagct ggcagtgaat gtgccactgt atgtcaacct catgaagaat 1080 gaagaggtct tggtatcagc ctatgccaat gatggtgctc cagaccatga aactgctagc 1140 aatcatgcaa ttcttcagct cttccaggga gaccagatat ggttacgtct gcacagggga 1200 gcaatttatg gaagtagctg gaaatattct acgttttcag gctatcttct ttatcaagat 1260 tga 1263 2 420 PRT Homo sapiens 2 Met Thr Gln Ile Gln Gly Thr Cys Asn Phe Met Gln Glu Ser Val Leu 1 5 10 15 Asp Phe Asp Lys Pro Ser Ser Ala Ile Pro Thr Ser Gln Pro Pro Ser 20 25 30 Ala Thr Pro Gly Ser Pro Val Ala Ser Lys Glu Gln Asn Leu Ser Ser 35 40 45 Gln Ser Asp Phe Leu Gln Glu Pro Leu Gln Val Phe Asn Val Asn Ala 50 55 60 Pro Leu Pro Pro Arg Lys Glu Gln Glu Ile Lys Glu Ser Pro Tyr Ser 65 70 75 80 Pro Gly Tyr Asn Gln Ser Phe Thr Thr Ala Ser Thr Gln Thr Pro Pro 85 90 95 Gln Cys Gln Leu Pro Ser Ile His Val Glu Gln Thr Val His Ser Gln 100 105 110 Glu Thr Ala Ala Asn Tyr His Pro Asp Gly Thr Ile Gln Val Ser Asn 115 120 125 Gly Ser Leu Ala Phe Tyr Pro Ala Gln Thr Asn Val Phe Pro Arg Pro 130 135 140 Thr Gln Pro Phe Val Asn Ser Arg Gly Ser Val Arg Gly Cys Thr Arg 145 150 155 160 Gly Gly Arg Leu Ile Thr Asn Ser Tyr Arg Ser Pro Gly Gly Tyr Lys 165 170 175 Gly Phe Asp Thr Tyr Arg Gly Leu Pro Ser Ile Ser Asn Gly Asn Tyr 180 185 190 Ser Gln Leu Gln Phe Gln Ala Arg Glu Tyr Ser Gly Ala Pro Tyr Ser 195 200 205 Gln Arg Asp Asn Phe Gln Gln Cys Tyr Lys Arg Gly Gly Thr Ser Gly 210 215 220 Gly Pro Arg Ala Asn Ser Arg Ala Gly Trp Ser Asp Ser Ser Gln Val 225 230 235 240 Ser Ser Pro Glu Arg Asp Asn Glu Thr Phe Asn Ser Gly Asp Ser Gly 245 250 255 Gln Gly Asp Ser Arg Ser Met Thr Pro Val Asp Val Pro Val Thr Asn 260 265 270 Pro Ala Ala Thr Ile Leu Pro Val His Val Tyr Pro Leu Pro Gln Gln 275 280 285 Met Arg Val Ala Phe Ser Ala Ala Arg Thr Ser Asn Leu Ala Pro Gly 290 295 300 Thr Leu Asp Gln Pro Ile Val Phe Asp Leu Leu Leu Asn Asn Leu Gly 305 310 315 320 Glu Thr Phe Asp Leu Gln Leu Gly Arg Phe Asn Cys Pro Val Asn Gly 325 330 335 Thr Tyr Val Phe Ile Phe His Met Leu Lys Leu Ala Val Asn Val Pro 340 345 350 Leu Tyr Val Asn Leu Met Lys Asn Glu Glu Val Leu Val Ser Ala Tyr 355 360 365 Ala Asn Asp Gly Ala Pro Asp His Glu Thr Ala Ser Asn His Ala Ile 370 375 380 Leu Gln Leu Phe Gln Gly Asp Gln Ile Trp Leu Arg Leu His Arg Gly 385 390 395 400 Ala Ile Tyr Gly Ser Ser Trp Lys Tyr Ser Thr Phe Ser Gly Tyr Leu 405 410 415 Leu Tyr Gln Asp 420 3 1230 DNA Mus musculus 3 atggtggtct ccccctgcaa gccaaagcca gcttctgcac ttgcttctcc aaatcctccc 60 ctgtcaaaga gcttccagtt acctcctgca agtgggagtt cagaagccat tagcacagca 120 ccttttcagg ccatgcagac agtgtttaat gttaatgcac ctctgcctcc acggaaagaa 180 caagaaatga aagaacctcc ttattcatct ggctacaatc aaaattttac ttcatcaagt 240 acacagacag tatcccaatg ccagctccca gctgtacaca tagaccagac aactcagcct 300 ccagagactg gtgcaggtta tcatcctgat ggaactgttc aagtaagcaa tggcagcctt 360 gccttttacc cagcacccac gagtatgttt cccagacctg ctcagccatt tatcagtagt 420 cgggggactc tgagagggtg ttcacatgga gggaggttac taatgagttc ctatcagtct 480 cctggtggct acaaaggttt tgatagttac agaggacttc cttcagtttc aagtgggaat 540 tacagccagc tgcagctgca agctagagaa tattctggaa cagcttactc tcaaagggat 600 aatttccagc agtgttataa aagatcaggg acatctagtg gtcttcaggc aaattcaaga 660 gcagggtgga gtgactcctc tcaggtgagc agcccagaaa gagacagcga gacttttaac 720 agtggagact ctgggctagg agactctcgg agcatgaccc cagtggatgt gccagtgaca 780 agcccagcag ccgccatcct gccagtccat atctatcccc tgcctcagca aatgcgagtt 840 gccttctcag ctgccagaac atccaatctg gctcctggaa ctttagacca acctattgtg 900 tttgatcttc tcctgaacaa cttgggagag acctttaatc ttcagcttgg tagattcaat 960 tgcccagtga atggcactta cgtgttcatt tttcacatgc taaagctggc tgtgaatgta 1020 ccactgtatg tcaacctgat gaagaatgag gaggtcttgg tgtcagccta tgccaacgat 1080 ggtgctccag accatgagac agcaagcaac catgccgttc tccagctcct ccagggagac 1140 cagatatggc tgcgcttaca caggggagcg atttatggaa gtagctggaa atactctaca 1200 ttttcaggct atcttcttta tcaagattaa 1230 4 409 PRT Mus musculus 4 Met Val Val Ser Pro Cys Lys Pro Lys Pro Ala Ser Ala Leu Ala Ser 1 5 10 15 Pro Asn Pro Pro Leu Ser Lys Ser Phe Gln Leu Pro Pro Ala Ser Gly 20 25 30 Ser Ser Glu Ala Ile Ser Thr Ala Pro Phe Gln Ala Met Gln Thr Val 35 40 45 Phe Asn Val Asn Ala Pro Leu Pro Pro Arg Lys Glu Gln Glu Met Lys 50 55 60 Glu Pro Pro Tyr Ser Ser Gly Tyr Asn Gln Asn Phe Thr Ser Ser Ser 65 70 75 80 Thr Gln Thr Val Ser Gln Cys Gln Leu Pro Ala Val His Ile Asp Gln 85 90 95 Thr Thr Gln Pro Pro Glu Thr Gly Ala Gly Tyr His Pro Asp Gly Thr 100 105 110 Val Gln Val Ser Asn Gly Ser Leu Ala Phe Tyr Pro Ala Pro Thr Ser 115 120 125 Met Phe Pro Arg Pro Ala Gln Pro Phe Ile Ser Ser Arg Gly Thr Leu 130 135 140 Arg Gly Cys Ser His Gly Gly Arg Leu Leu Met Ser Ser Tyr Gln Ser 145 150 155 160 Pro Gly Gly Tyr Lys Gly Phe Asp Ser Tyr Arg Gly Leu Pro Ser Val 165 170 175 Ser Ser Gly Asn Tyr Ser Gln Leu Gln Leu Gln Ala Arg Glu Tyr Ser 180 185 190 Gly Thr Ala Tyr Ser Gln Arg Asp Asn Phe Gln Gln Cys Tyr Lys Arg 195 200 205 Ser Gly Thr Ser Ser Gly Leu Gln Ala Asn Ser Arg Ala Gly Trp Ser 210 215 220 Asp Ser Ser Gln Val Ser Ser Pro Glu Arg Asp Ser Glu Thr Phe Asn 225 230 235 240 Ser Gly Asp Ser Gly Leu Gly Asp Ser Arg Ser Met Thr Pro Val Asp 245 250 255 Val Pro Val Thr Ser Pro Ala Ala Ala Ile Leu Pro Val His Ile Tyr 260 265 270 Pro Leu Pro Gln Gln Met Arg Val Ala Phe Ser Ala Ala Arg Thr Ser 275 280 285 Asn Leu Ala Pro Gly Thr Leu Asp Gln Pro Ile Val Phe Asp Leu Leu 290 295 300 Leu Asn Asn Leu Gly Glu Thr Phe Asn Leu Gln Leu Gly Arg Phe Asn 305 310 315 320 Cys Pro Val Asn Gly Thr Tyr Val Phe Ile Phe His Met Leu Lys Leu 325 330 335 Ala Val Asn Val Pro Leu Tyr Val Asn Leu Met Lys Asn Glu Glu Val 340 345 350 Leu Val Ser Ala Tyr Ala Asn Asp Gly Ala Pro Asp His Glu Thr Ala 355 360 365 Ser Asn His Ala Val Leu Gln Leu Leu Gln Gly Asp Gln Ile Trp Leu 370 375 380 Arg Leu His Arg Gly Ala Ile Tyr Gly Ser Ser Trp Lys Tyr Ser Thr 385 390 395 400 Phe Ser Gly Tyr Leu Leu Tyr Gln Asp 405 5 993 DNA Homo sapiens 5 atgggaaaac tatgcctggg gccgacgctc tgcccggctg ctgccgctga ggaaagccgg 60 gacgcggagc cccgccgaga gcttctttgc tccggacgcc cctggacgtg gcgggcagcc 120 gcgagggtaa ccaccatgat cccctgggtg ctcctggcct gtgccctccc ctgtgctgct 180 gacccactgc ttggcgcctt tgctcgcagg gacttccgga aaggctcccc tcaactggtc 240 tgcagcctgc ctggccccca gggcccaccc ggccccccag gagccccagg gccctcagga 300 atgatgggac gaatgggctt tcctggcaaa gacggccaag atggacacga cggcgaccgg 360 ggggacagcg gagaggaagg tccacctggc cggacaggta accggggaaa gccaggacca 420 aagggcaaag ccggggccat tgggcgggct ggcccccgtg gccccaaggg ggtcaacggt 480 acccccggga agcatggcac accaggcaag aaggggccca agggcaagaa gggggagcca 540 ggcctcccag gcccctgcag ctgtggcagt ggccatacca agtcagcttt ctcggtggca 600 gtgaccaaga gctacccacg ggagcggctg cccatcaagt ttgacaagat tctgatgaac 660 gagggtggcc actacaatgc ttccagcggc aagttcgtct gcggcgtgcc tgggatctac 720 tacttcacct acgacatcac gctggccaac aagcacctgg ccatcggcct ggtgcacaac 780 ggccagtacc gcatccggac ctttgatgcc aacaccggca accacgatgt ggcctcaggc 840 tccaccatcc tggctctcaa gcagggtgac gaagtttggc tgcagatctt ctactcagag 900 cagaacgggc tcttctatga cccttactgg acagacagcc tctttacggg cttcctaatc 960 tatgccgacc aggatgaccc caacgaggta tag 993 6 330 PRT Homo sapiens 6 Met Gly Lys Leu Cys Leu Gly Pro Thr Leu Cys Pro Ala Ala Ala Ala 1 5 10 15 Glu Glu Ser Arg Asp Ala Glu Pro Arg Arg Glu Leu Leu Cys Ser Gly 20 25 30 Arg Pro Trp Thr Trp Arg Ala Ala Ala Arg Val Thr Thr Met Ile Pro 35 40 45 Trp Val Leu Leu Ala Cys Ala Leu Pro Cys Ala Ala Asp Pro Leu Leu 50 55 60 Gly Ala Phe Ala Arg Arg Asp Phe Arg Lys Gly Ser Pro Gln Leu Val 65 70 75 80 Cys Ser Leu Pro Gly Pro Gln Gly Pro Pro Gly Pro Pro Gly Ala Pro 85 90 95 Gly Pro Ser Gly Met Met Gly Arg Met Gly Phe Pro Gly Lys Asp Gly 100 105 110 Gln Asp Gly His Asp Gly Asp Arg Gly Asp Ser Gly Glu Glu Gly Pro 115 120 125 Pro Gly Arg Thr Gly Asn Arg Gly Lys Pro Gly Pro Lys Gly Lys Ala 130 135 140 Gly Ala Ile Gly Arg Ala Gly Pro Arg Gly Pro Lys Gly Val Asn Gly 145 150 155 160 Thr Pro Gly Lys His Gly Thr Pro Gly Lys Lys Gly Pro Lys Gly Lys 165 170 175 Lys Gly Glu Pro Gly Leu Pro Gly Pro Cys Ser Cys Gly Ser Gly His 180 185 190 Thr Lys Ser Ala Phe Ser Val Ala Val Thr Lys Ser Tyr Pro Arg Glu 195 200 205 Arg Leu Pro Ile Lys Phe Asp Lys Ile Leu Met Asn Glu Gly Gly His 210 215 220 Tyr Asn Ala Ser Ser Gly Lys Phe Val Cys Gly Val Pro Gly Ile Tyr 225 230 235 240 Tyr Phe Thr Tyr Asp Ile Thr Leu Ala Asn Lys His Leu Ala Ile Gly 245 250 255 Leu Val His Asn Gly Gln Tyr Arg Ile Arg Thr Phe Asp Ala Asn Thr 260 265 270 Gly Asn His Asp Val Ala Ser Gly Ser Thr Ile Leu Ala Leu Lys Gln 275 280 285 Gly Asp Glu Val Trp Leu Gln Ile Phe Tyr Ser Glu Gln Asn Gly Leu 290 295 300 Phe Tyr Asp Pro Tyr Trp Thr Asp Ser Leu Phe Thr Gly Phe Leu Ile 305 310 315 320 Tyr Ala Asp Gln Asp Asp Pro Asn Glu Val 325 330 7 885 DNA Mus musculus 7 atgacaattt ttaaaaaggt gacaaccatg atctcctggg tactcttggc ctgtgccctt 60 ccgtgtgctg ctgacccaat gcttggtgcc tttgctcgca gggacttcca gaaggggggt 120 cctcaactag tttgcagcct gcctggtccc caaggcccac ctggccctcc aggagcacca 180 ggatcctcag gagtggtggg aagaatgggt ttccctggga aagacggcca agatggccag 240 gacggagacc ggggggacag tggagaagaa ggtccacctg gcaggacagg caaccgtgga 300 aaacaaggac caaagggcaa agctggggcc attggcagag ctggccctcg aggacccaag 360 ggggtcagtg gtacccccgg gaagcatggc acaccgggca agaagggacc taagggcaaa 420 aaaggggagc ctggcctccc aggcccctgc agctgcggca gtagccgagc caagtcggcc 480 ttttccgtgg cggtaaccaa gagctaccca cgcgagagac tgcctatcaa gtttgacaag 540 attctgatga acgagggtgg ccactacaac gcgtccagtg gcaagttcgt ctgcagcgtg 600 ccggggatct attactttac ctatgacatt acgctggcca acaaacacct ggccatcggc 660 ctggtgcaca atggtcagta ccgcattcgg acttttgatg ccaacacggg caaccacgac 720 gtggcctcgg gctccaccat cctagctctc aaggagggtg atgaagtctg gctgcagatc 780 ttctactcag agcagaatgg cctcttctac gacccttact ggaccgacag cctgttcacc 840 ggcttcctca tctacgctga ccaaggagac cccaacgagg tatag 885 8 294 PRT Mus musculus 8 Met Thr Ile Phe Lys Lys Val Thr Thr Met Ile Ser Trp Val Leu Leu 1 5 10 15 Ala Cys Ala Leu Pro Cys Ala Ala Asp Pro Met Leu Gly Ala Phe Ala 20 25 30 Arg Arg Asp Phe Gln Lys Gly Gly Pro Gln Leu Val Cys Ser Leu Pro 35 40 45 Gly Pro Gln Gly Pro Pro Gly Pro Pro Gly Ala Pro Gly Ser Ser Gly 50 55 60 Val Val Gly Arg Met Gly Phe Pro Gly Lys Asp Gly Gln Asp Gly Gln 65 70 75 80 Asp Gly Asp Arg Gly Asp Ser Gly Glu Glu Gly Pro Pro Gly Arg Thr 85 90 95 Gly Asn Arg Gly Lys Gln Gly Pro Lys Gly Lys Ala Gly Ala Ile Gly 100 105 110 Arg Ala Gly Pro Arg Gly Pro Lys Gly Val Ser Gly Thr Pro Gly Lys 115 120 125 His Gly Thr Pro Gly Lys Lys Gly Pro Lys Gly Lys Lys Gly Glu Pro 130 135 140 Gly Leu Pro Gly Pro Cys Ser Cys Gly Ser Ser Arg Ala Lys Ser Ala 145 150 155 160 Phe Ser Val Ala Val Thr Lys Ser Tyr Pro Arg Glu Arg Leu Pro Ile 165 170 175 Lys Phe Asp Lys Ile Leu Met Asn Glu Gly Gly His Tyr Asn Ala Ser 180 185 190 Ser Gly Lys Phe Val Cys Ser Val Pro Gly Ile Tyr Tyr Phe Thr Tyr 195 200 205 Asp Ile Thr Leu Ala Asn Lys His Leu Ala Ile Gly Leu Val His Asn 210 215 220 Gly Gln Tyr Arg Ile Arg Thr Phe Asp Ala Asn Thr Gly Asn His Asp 225 230 235 240 Val Ala Ser Gly Ser Thr Ile Leu Ala Leu Lys Glu Gly Asp Glu Val 245 250 255 Trp Leu Gln Ile Phe Tyr Ser Glu Gln Asn Gly Leu Phe Tyr Asp Pro 260 265 270 Tyr Trp Thr Asp Ser Leu Phe Thr Gly Phe Leu Ile Tyr Ala Asp Gln 275 280 285 Gly Asp Pro Asn Glu Val 290 9 3162 DNA Homo sapiens 9 atgtggcagc ccagacggcc ctggccccgc gtgccctggc gctgggcgct ggcgctgctg 60 gccctggttg gcgcggggct gtgccacgcc ggcccgcagc ccgggtatcc cgcgcggccc 120 agcgccagga acaagaactg gtgcgcctac atcgtgaaca agaatgtgag ctgctccgtg 180 ctggagggaa gtgagagttt tattcaggct cagtacaact gtgcctggaa ccagatgccc 240 tgtccgtcgg cgctggtgta tcgagtgaac ttcagaccta gatatgtcac taggtataag 300 acagtgacac agttggaatg gaggtgctgt cctggcttta gagggggaga ttgccaagaa 360 ggtcccaaag accccgtgaa gaccctccgc cccacgccgg ctcggcctcg aaayagcttg 420 aagaaagcca cagataatga acccagccaa ttctcagagc ccaggaagac tttgtcccca 480 actggtacag cacaaccaag ctggggggta gatccaaaag aggggcctca ggaacttcag 540 gaaaagaaga tacaggtgct agaggagaag gttcttcgac tcacaaggac ggttcttgac 600 ctccagtctt cccttgctgg agtgagtgaa aatctcaaac atgccactca ggatgatgcc 660 agtagaacac gggcaccagg gctcagcagc cagcacccca agcctgacac cactgttagt 720 ggagacacag aaacgggcca gagtcctggt gtcttcaaca ctaaggaatc tggcatgaag 780 gacatcaagt ctgaattggc tgaagtcaaa gatactctaa agaacaaaag tgacaagctg 840 gaagagctgg atggaaaagt gaagggctac gaagggcagc tcagacagct ccaggaagca 900 gctcagggcc cgacggtgac catgacaacc aacgaactct accaagccta tgtggacagt 960 aagatcgacg ccctgagaga ggagctcatg gagggcatgg acagaaagct ggctgacctg 1020 aaaaactcat gtgagtacaa gctcactggc ctccagcagc agtgtgatga ctatgggagc 1080 agctacctgg gagtgataga gctcataggg gagaaggaaa caagcctgag aaaagaaata 1140 aataacctcc gagcccggct acaggagcct tcagcccagg caaattgctg cgacagtgaa 1200 aagaatggtg acattggtca acagatcaag acattggacc agaaaatcga gagagttgct 1260 gaagccacca gaatgctgaa tggaagactg gacaatgagt ttgaccgcct tatagttcca 1320 gagccagatg tggattttga tgcaaaatgg aatgaactcg atgcaaggat caatgtgacg 1380 gagaagaacg ctgaagaaca ttgcttttac attgaggaaa cccttcgggg cgccattaat 1440 ggagaggtgg gtgacttgaa gcagcttgtt gatcagaaaa tacagtctct ggaagaccgt 1500 ctggggagcg ttctcctaca gatgaccaat aacactggtg cagagctcag tcccccaggg 1560 gcagcagccc tgccaggagt gtcagggtca ggagatgaac gggtcatgat ggaattaaac 1620 cacctgaagg acggagttca agttgttgaa gacatttgcc tgctgaacat ccagggaaag 1680 cctcatggga tggaaggtgc cttgccaaac agggaagacc gcgcagtacg cgacagcctg 1740 caccttttga aatctctcaa cgacacgatg cacaggaagt ttcaagaaac cgaacaaacc 1800 atccagaaac ttcaacagga ttttagtttt ctttattctc aattaaacca cacagaaaat 1860 gatgtgactc atcttcaaaa ggaaatgagc aattgtagag caggtgaaaa cgctggcatg 1920 ggtaggttca ctaaggtggg tgagcaagaa aggacagtgg acaccctgcc gtccccccag 1980 caccccgtgg ctcattgctg cagtcagctg gaggagaggt ggcagaggtt gcagagccag 2040 gtcatctcgg agctggatgc ttgtaaggaa tgcacgcagg gggtccagag ggaggtctcc 2100 atggtggagg gcagggtgtc tcatatggag aaaacttgca gcaagctgga ctctatctca 2160 ggaaatcttc agaggatcaa ggaggggctc aacaagcatg tcagcagcct gtggaactgt 2220 gtcaggcaga tgaacggaac gctcaggtcg cattccagag acatttctgg cctgaagaat 2280 tcagtccagc agttctacag ccacgtcttc cagatttcta ctgatttgca agatctggtc 2340 aaatttcagc catcagcaaa ggcgccctcg cccccgccgc ccgcagaggc cccgaaggag 2400 ccgctgcagc ccgagcccgc cccgccgagg cccagcggcc ccgcaaccgc agaggaccct 2460 gggcgacggc ccgtcctgcc ccagcggccc cccgaggaga ggccgcccca gccgccaggc 2520 tccaccgggg tcatcgcgga gacgggccag gccgggcccc ccgcaggcgc aggcgtgtct 2580 gggcggggtc tgccgcgggg cgtggacggc cagaccggga gcggcaccgt ccccggcgca 2640 gaaggcttcg cgggcgcacc aggatacccg aagtcacctc ctgtagcttc cccaggagct 2700 ccggtgcctt ctctggtgtc tttttctgcg gggctcaccc agaagccttt ccccagtgat 2760 gggggcgttg tcctctttaa caaagtgctg gtgaacgacg gggatgttta caaccccagc 2820 accggggtct tcacggctcc ttatgatggg cgctacctga tcacggccac cctcaccccc 2880 gagagagacg cctacgtgga agcagtgctg tcggtctcca acgccagcgt ggcccagctg 2940 cataccgctg ggtacaggag agagttcctg gaataccacc gccctccagg agctttgcat 3000 acctgcgggg gcccgggggc attccacctc atcgtgcacc tgaaggcggg agatgcagtc 3060 aacgtcgtgg tgactggggg caagctggct cacacagact ttgatgaaat gtactccaca 3120 tttagtgggg ttttcttata tcctttcctt tcccacctct aa 3162 10 1053 PRT Homo sapiens 10 Met Trp Gln Pro Arg Arg Pro Trp Pro Arg Val Pro Trp Arg Trp Ala 1 5 10 15 Leu Ala Leu Leu Ala Leu Val Gly Ala Gly Leu Cys His Ala Gly Pro 20 25 30 Gln Pro Gly Tyr Pro Ala Arg Pro Ser Ala Arg Asn Lys Asn Trp Cys 35 40 45 Ala Tyr Ile Val Asn Lys Asn Val Ser Cys Ser Val Leu Glu Gly Ser 50 55 60 Glu Ser Phe Ile Gln Ala Gln Tyr Asn Cys Ala Trp Asn Gln Met Pro 65 70 75 80 Cys Pro Ser Ala Leu Val Tyr Arg Val Asn Phe Arg Pro Arg Tyr Val 85 90 95 Thr Arg Tyr Lys Thr Val Thr Gln Leu Glu Trp Arg Cys Cys Pro Gly 100 105 110 Phe Arg Gly Gly Asp Cys Gln Glu Gly Pro Lys Asp Pro Val Lys Thr 115 120 125 Leu Arg Pro Thr Pro Ala Arg Pro Arg Asn Ser Leu Lys Lys Ala Thr 130 135 140 Asp Asn Glu Pro Ser Gln Phe Ser Glu Pro Arg Lys Thr Leu Ser Pro 145 150 155 160 Thr Gly Thr Ala Gln Pro Ser Trp Gly Val Asp Pro Lys Glu Gly Pro 165 170 175 Gln Glu Leu Gln Glu Lys Lys Ile Gln Val Leu Glu Glu Lys Val Leu 180 185 190 Arg Leu Thr Arg Thr Val Leu Asp Leu Gln Ser Ser Leu Ala Gly Val 195 200 205 Ser Glu Asn Leu Lys His Ala Thr Gln Asp Asp Ala Ser Arg Thr Arg 210 215 220 Ala Pro Gly Leu Ser Ser Gln His Pro Lys Pro Asp Thr Thr Val Ser 225 230 235 240 Gly Asp Thr Glu Thr Gly Gln Ser Pro Gly Val Phe Asn Thr Lys Glu 245 250 255 Ser Gly Met Lys Asp Ile Lys Ser Glu Leu Ala Glu Val Lys Asp Thr 260 265 270 Leu Lys Asn Lys Ser Asp Lys Leu Glu Glu Leu Asp Gly Lys Val Lys 275 280 285 Gly Tyr Glu Gly Gln Leu Arg Gln Leu Gln Glu Ala Ala Gln Gly Pro 290 295 300 Thr Val Thr Met Thr Thr Asn Glu Leu Tyr Gln Ala Tyr Val Asp Ser 305 310 315 320 Lys Ile Asp Ala Leu Arg Glu Glu Leu Met Glu Gly Met Asp Arg Lys 325 330 335 Leu Ala Asp Leu Lys Asn Ser Cys Glu Tyr Lys Leu Thr Gly Leu Gln 340 345 350 Gln Gln Cys Asp Asp Tyr Gly Ser Ser Tyr Leu Gly Val Ile Glu Leu 355 360 365 Ile Gly Glu Lys Glu Thr Ser Leu Arg Lys Glu Ile Asn Asn Leu Arg 370 375 380 Ala Arg Leu Gln Glu Pro Ser Ala Gln Ala Asn Cys Cys Asp Ser Glu 385 390 395 400 Lys Asn Gly Asp Ile Gly Gln Gln Ile Lys Thr Leu Asp Gln Lys Ile 405 410 415 Glu Arg Val Ala Glu Ala Thr Arg Met Leu Asn Gly Arg Leu Asp Asn 420 425 430 Glu Phe Asp Arg Leu Ile Val Pro Glu Pro Asp Val Asp Phe Asp Ala 435 440 445 Lys Trp Asn Glu Leu Asp Ala Arg Ile Asn Val Thr Glu Lys Asn Ala 450 455 460 Glu Glu His Cys Phe Tyr Ile Glu Glu Thr Leu Arg Gly Ala Ile Asn 465 470 475 480 Gly Glu Val Gly Asp Leu Lys Gln Leu Val Asp Gln Lys Ile Gln Ser 485 490 495 Leu Glu Asp Arg Leu Gly Ser Val Leu Leu Gln Met Thr Asn Asn Thr 500 505 510 Gly Ala Glu Leu Ser Pro Pro Gly Ala Ala Ala Leu Pro Gly Val Ser 515 520 525 Gly Ser Gly Asp Glu Arg Val Met Met Glu Leu Asn His Leu Lys Asp 530 535 540 Gly Val Gln Val Val Glu Asp Ile Cys Leu Leu Asn Ile Gln Gly Lys 545 550 555 560 Pro His Gly Met Glu Gly Ala Leu Pro Asn Arg Glu Asp Arg Ala Val 565 570 575 Arg Asp Ser Leu His Leu Leu Lys Ser Leu Asn Asp Thr Met His Arg 580 585 590 Lys Phe Gln Glu Thr Glu Gln Thr Ile Gln Lys Leu Gln Gln Asp Phe 595 600 605 Ser Phe Leu Tyr Ser Gln Leu Asn His Thr Glu Asn Asp Val Thr His 610 615 620 Leu Gln Lys Glu Met Ser Asn Cys Arg Ala Gly Glu Asn Ala Gly Met 625 630 635 640 Gly Arg Phe Thr Lys Val Gly Glu Gln Glu Arg Thr Val Asp Thr Leu 645 650 655 Pro Ser Pro Gln His Pro Val Ala His Cys Cys Ser Gln Leu Glu Glu 660 665 670 Arg Trp Gln Arg Leu Gln Ser Gln Val Ile Ser Glu Leu Asp Ala Cys 675 680 685 Lys Glu Cys Thr Gln Gly Val Gln Arg Glu Val Ser Met Val Glu Gly 690 695 700 Arg Val Ser His Met Glu Lys Thr Cys Ser Lys Leu Asp Ser Ile Ser 705 710 715 720 Gly Asn Leu Gln Arg Ile Lys Glu Gly Leu Asn Lys His Val Ser Ser 725 730 735 Leu Trp Asn Cys Val Arg Gln Met Asn Gly Thr Leu Arg Ser His Ser 740 745 750 Arg Asp Ile Ser Gly Leu Lys Asn Ser Val Gln Gln Phe Tyr Ser His 755 760 765 Val Phe Gln Ile Ser Thr Asp Leu Gln Asp Leu Val Lys Phe Gln Pro 770 775 780 Ser Ala Lys Ala Pro Ser Pro Pro Pro Pro Ala Glu Ala Pro Lys Glu 785 790 795 800 Pro Leu Gln Pro Glu Pro Ala Pro Pro Arg Pro Ser Gly Pro Ala Thr 805 810 815 Ala Glu Asp Pro Gly Arg Arg Pro Val Leu Pro Gln Arg Pro Pro Glu 820 825 830 Glu Arg Pro Pro Gln Pro Pro Gly Ser Thr Gly Val Ile Ala Glu Thr 835 840 845 Gly Gln Ala Gly Pro Pro Ala Gly Ala Gly Val Ser Gly Arg Gly Leu 850 855 860 Pro Arg Gly Val Asp Gly Gln Thr Gly Ser Gly Thr Val Pro Gly Ala 865 870 875 880 Glu Gly Phe Ala Gly Ala Pro Gly Tyr Pro Lys Ser Pro Pro Val Ala 885 890 895 Ser Pro Gly Ala Pro Val Pro Ser Leu Val Ser Phe Ser Ala Gly Leu 900 905 910 Thr Gln Lys Pro Phe Pro Ser Asp Gly Gly Val Val Leu Phe Asn Lys 915 920 925 Val Leu Val Asn Asp Gly Asp Val Tyr Asn Pro Ser Thr Gly Val Phe 930 935 940 Thr Ala Pro Tyr Asp Gly Arg Tyr Leu Ile Thr Ala Thr Leu Thr Pro 945 950 955 960 Glu Arg Asp Ala Tyr Val Glu Ala Val Leu Ser Val Ser Asn Ala Ser 965 970 975 Val Ala Gln Leu His Thr Ala Gly Tyr Arg Arg Glu Phe Leu Glu Tyr 980 985 990 His Arg Pro Pro Gly Ala Leu His Thr Cys Gly Gly Pro Gly Ala Phe 995 1000 1005 His Leu Ile Val His Leu Lys Ala Gly Asp Ala Val Asn Val Val 1010 1015 1020 Val Thr Gly Gly Lys Leu Ala His Thr Asp Phe Asp Glu Met Tyr 1025 1030 1035 Ser Thr Phe Ser Gly Val Phe Leu Tyr Pro Phe Leu Ser His Leu 1040 1045 1050 11 444 DNA Mus musculus 11 atgcagtttg tgtgtctcac acatttgtcc agtttctctg tactagccct tggtctgcca 60 aggggagtct ctggactttc agaagatagg caggtccaca tgctctggct tctctctgcc 120 ctaggggtgc cgctgcccac tctggtgtcc ttttcagccg gtcttaccca gaagcctttt 180 cccagcgatg gaggcgttgt tctcttcaat aaggtgctgg tgaacgatgg ggatgtatac 240 aaccccaaca ctgggatctt caccgcacca tacgacgggc gctacttgat cacagccacc 300 ctcacccctg agagagacac ctatgtggaa gccgtcctgt ctgtctccaa cgccagtgtt 360 gcccagctgc acacggctgg gtacaggaga gagttcctgg aataccatcg tcccccttgg 420 gctgtgcata cctgtggggg cccg 444 12 148 PRT Mus musculus 12 Met Gln Phe Val Cys Leu Thr His Leu Ser Ser Phe Ser Val Leu Ala 1 5 10 15 Leu Gly Leu Pro Arg Gly Val Ser Gly Leu Ser Glu Asp Arg Gln Val 20 25 30 His Met Leu Trp Leu Leu Ser Ala Leu Gly Val Pro Leu Pro Thr Leu 35 40 45 Val Ser Phe Ser Ala Gly Leu Thr Gln Lys Pro Phe Pro Ser Asp Gly 50 55 60 Gly Val Val Leu Phe Asn Lys Val Leu Val Asn Asp Gly Asp Val Tyr 65 70 75 80 Asn Pro Asn Thr Gly Ile Phe Thr Ala Pro Tyr Asp Gly Arg Tyr Leu 85 90 95 Ile Thr Ala Thr Leu Thr Pro Glu Arg Asp Thr Tyr Val Glu Ala Val 100 105 110 Leu Ser Val Ser Asn Ala Ser Val Ala Gln Leu His Thr Ala Gly Tyr 115 120 125 Arg Arg Glu Phe Leu Glu Tyr His Arg Pro Pro Trp Ala Val His Thr 130 135 140 Cys Gly Gly Pro 145 13 990 DNA Homo sapiens 13 atgctgccgc ttctgctggg cctgctgggc ccagcggcct gctgggccct gggcccgacc 60 cccggcccgg gatcctctga gctgcgctcg gccttctcgg cggcacgcac cacccccctg 120 gagggcacgt cggagatggc ggtgaccttc gacaaggtgt acgtgaacat cgggggcgac 180 ttcgatgtgg ccaccggcca gtttcgctgc cgcgtgcccg gcgcctactt cttctccttc 240 acggctggca aggccccgca caagagcctg tcggtgatgc tggtgcgaaa ccgcgacgag 300 gtgcaggcgc tggccttcga cgagcagcgg cggccaagcg cgcggcgcgc agccagccag 360 agcgccatgc tgcagctcga ctacggcgac acagtgtggc tgcggctgca tggcgccccg 420 cactacgcgc taggcgcgcc cggcgccacc ttcagcggct acctagtcta cgccgacgcc 480 gacgctgacg cgcctgcgcg cgggccgccc gcgccccccg agccgcgctc ggccttctcg 540 gcggcgcgca cgcgcagctt ggtgggctcg gacgctggcc ccgggccgcg gcaccaacca 600 ctcgccttcg acaccgagtt cgtcaacatt ggcggcgact tcgacgcggc ggccggcgtg 660 ttccgctgcc gtctgcccgg cgcctacttc ttctccttca cgctgggcaa gctgccgcgt 720 aagacgctgt cggttaagct gatgaagaac cgcgacgagg tgcaggccat gatttacgac 780 gacggcgcgt cgcggcgccg cgagatgcag agccagagcg tgatgctggc cctgcggcgc 840 ggcgacgccg tctggctgct cagccacgac cacgacggct acggcgccta cagcaaccac 900 ggcaagtaca tcaccttctc cggcttcctg gtgtaccccg acctcgcccc cgccgccccg 960 ccgggcctcg gggcctcgga gctactgtga 990 14 329 PRT Homo sapiens 14 Met Leu Pro Leu Leu Leu Gly Leu Leu Gly Pro Ala Ala Cys Trp Ala 1 5 10 15 Leu Gly Pro Thr Pro Gly Pro Gly Ser Ser Glu Leu Arg Ser Ala Phe 20 25 30 Ser Ala Ala Arg Thr Thr Pro Leu Glu Gly Thr Ser Glu Met Ala Val 35 40 45 Thr Phe Asp Lys Val Tyr Val Asn Ile Gly Gly Asp Phe Asp Val Ala 50 55 60 Thr Gly Gln Phe Arg Cys Arg Val Pro Gly Ala Tyr Phe Phe Ser Phe 65 70 75 80 Thr Ala Gly Lys Ala Pro His Lys Ser Leu Ser Val Met Leu Val Arg 85 90 95 Asn Arg Asp Glu Val Gln Ala Leu Ala Phe Asp Glu Gln Arg Arg Pro 100 105 110 Ser Ala Arg Arg Ala Ala Ser Gln Ser Ala Met Leu Gln Leu Asp Tyr 115 120 125 Gly Asp Thr Val Trp Leu Arg Leu His Gly Ala Pro His Tyr Ala Leu 130 135 140 Gly Ala Pro Gly Ala Thr Phe Ser Gly Tyr Leu Val Tyr Ala Asp Ala 145 150 155 160 Asp Ala Asp Ala Pro Ala Arg Gly Pro Pro Ala Pro Pro Glu Pro Arg 165 170 175 Ser Ala Phe Ser Ala Ala Arg Thr Arg Ser Leu Val Gly Ser Asp Ala 180 185 190 Gly Pro Gly Pro Arg His Gln Pro Leu Ala Phe Asp Thr Glu Phe Val 195 200 205 Asn Ile Gly Gly Asp Phe Asp Ala Ala Ala Gly Val Phe Arg Cys Arg 210 215 220 Leu Pro Gly Ala Tyr Phe Phe Ser Phe Thr Leu Gly Lys Leu Pro Arg 225 230 235 240 Lys Thr Leu Ser Val Lys Leu Met Lys Asn Arg Asp Glu Val Gln Ala 245 250 255 Met Ile Tyr Asp Asp Gly Ala Ser Arg Arg Arg Glu Met Gln Ser Gln 260 265 270 Ser Val Met Leu Ala Leu Arg Arg Gly Asp Ala Val Trp Leu Leu Ser 275 280 285 His Asp His Asp Gly Tyr Gly Ala Tyr Ser Asn His Gly Lys Tyr Ile 290 295 300 Thr Phe Ser Gly Phe Leu Val Tyr Pro Asp Leu Ala Pro Ala Ala Pro 305 310 315 320 Pro Gly Leu Gly Ala Ser Glu Leu Leu 325 15 981 DNA Mus musculus 15 atgctgctgc tcttgctggg cttcctaggc ccggcggcct gctgggcact gggcccggct 60 ggccctggct cctcggagct gcggtcagcc ttctcggcgg ctcgcaccac cccgctggag 120 ggcacgtcgg agatggcggt gaccttcgac aaggtgtacg tgaacatcgg gggtgacttc 180 gacgcagcca ccgggcggtt ccgctgtcgc gtgccgggcg cctacttctt ctccttcacg 240 gccggcaagg ccccgcacaa gagcctgtcg gtgatgctgg tgcgcaaccg cgacgaggtg 300 caggcgctgg ctttcgacga gcagcgacgg ccaggcgcgc ggcgcgcggc cagccagagc 360 gccatgctgc agctcgacta cggcgacacg gtgtggctgc ggctgcacgg cgctccgcag 420 tacgcgctcg gcgcgccggg cgccaccttc agcggctacc tggtgtacgc ggacgccgac 480 gccgacgcgc ctgcgcgcgg ccccgcggcc ccggagccgc gctcggcctt ctccgcggcg 540 cgcacgcgca gcctggtggg ctcggacgcc gcccccggcc cgcgccaccg gccgttggcc 600 ttcgacaccg agctggtaaa cataggtggc gacttcgacg cggcggccgg cgtgttccgc 660 tgccgcctgc cgggagccta tttcttctcc ttcacgctgg gcaagctgcc gcgcaagacg 720 ctgtcggtga agctgatgaa gaaccgcgac gaggtgcagg ccatgattta cgacgacggc 780 gcttcgaggc gccgtgagat gcagagtcag agcgtgatgc tgccgctgcg gcgcggcgac 840 gccgtctggc tacttagcca cgatcacgat ggctatggcg cctacagcaa ccacggcaag 900 tacatcactt tctcaggctt cctggtgtac cctgacctcg ccgccgccgg cccgccggcc 960 ctcaagcccc cagagctctg a 981 16 326 PRT Mus musculus 16 Met Leu Leu Leu Leu Leu Gly Phe Leu Gly Pro Ala Ala Cys Trp Ala 1 5 10 15 Leu Gly Pro Ala Gly Pro Gly Ser Ser Glu Leu Arg Ser Ala Phe Ser 20 25 30 Ala Ala Arg Thr Thr Pro Leu Glu Gly Thr Ser Glu Met Ala Val Thr 35 40 45 Phe Asp Lys Val Tyr Val Asn Ile Gly Gly Asp Phe Asp Ala Ala Thr 50 55 60 Gly Arg Phe Arg Cys Arg Val Pro Gly Ala Tyr Phe Phe Ser Phe Thr 65 70 75 80 Ala Gly Lys Ala Pro His Lys Ser Leu Ser Val Met Leu Val Arg Asn 85 90 95 Arg Asp Glu Val Gln Ala Leu Ala Phe Asp Glu Gln Arg Arg Pro Gly 100 105 110 Ala Arg Arg Ala Ala Ser Gln Ser Ala Met Leu Gln Leu Asp Tyr Gly 115 120 125 Asp Thr Val Trp Leu Arg Leu His Gly Ala Pro Gln Tyr Ala Leu Gly 130 135 140 Ala Pro Gly Ala Thr Phe Ser Gly Tyr Leu Val Tyr Ala Asp Ala Asp 145 150 155 160 Ala Asp Ala Pro Ala Arg Gly Pro Ala Ala Pro Glu Pro Arg Ser Ala 165 170 175 Phe Ser Ala Ala Arg Thr Arg Ser Leu Val Gly Ser Asp Ala Ala Pro 180 185 190 Gly Pro Arg His Arg Pro Leu Ala Phe Asp Thr Glu Leu Val Asn Ile 195 200 205 Gly Gly Asp Phe Asp Ala Ala Ala Gly Val Phe Arg Cys Arg Leu Pro 210 215 220 Gly Ala Tyr Phe Phe Ser Phe Thr Leu Gly Lys Leu Pro Arg Lys Thr 225 230 235 240 Leu Ser Val Lys Leu Met Lys Asn Arg Asp Glu Val Gln Ala Met Ile 245 250 255 Tyr Asp Asp Gly Ala Ser Arg Arg Arg Glu Met Gln Ser Gln Ser Val 260 265 270 Met Leu Pro Leu Arg Arg Gly Asp Ala Val Trp Leu Leu Ser His Asp 275 280 285 His Asp Gly Tyr Gly Ala Tyr Ser Asn His Gly Lys Tyr Ile Thr Phe 290 295 300 Ser Gly Phe Leu Val Tyr Pro Asp Leu Ala Ala Ala Gly Pro Pro Ala 305 310 315 320 Leu Lys Pro Pro Glu Leu 325 17 732 DNA Homo sapiens 17 atgaggccac tcctcgtcct gctgctcctg ggcctggcgg ccggctcgcc cccactggac 60 gacaacaaga tccccagcct ctgcccgggg caccccggcc ttccaggcac gccgggccac 120 catggcagcc agggcttgcc gggccgcgat ggccgcgacg gccgcgacgg cgcgcccggg 180 gctccgggag agaaaggcga gggcgggagg ccgggactgc cgggacctcg aggggacccc 240 gggccgcgag gagaggcggg acccgcgggg cccaccgggc ctgccgggga gtgctcggtg 300 cctccgcgat ccgccttcag cgccaagcgc tccgagagcc gggtgcctcc gccgtctgac 360 gcacccttgc ccttcgaccg cgtgctggtg aacgagcagg gacattacga cgccgtcacc 420 ggcaagttca cctgccaggt gcctggggtc tactacttcg ccgtccatgc caccgtctac 480 cgggccagcc tgcagtttga tctggtgaag aatggcgaat ccattgcctc tttcttccag 540 tttttcgggg ggtggcccaa gccagcctcg ctctcggggg gggccatggt gaggctggag 600 cctgaggacc aagtgtgggt gcaggtgggt gtgggtgact acattggcat ctatgccagc 660 atcaagacag acagcacctt ctccggattt ctggtgtact ccgactggca cagctcccca 720 gtctttgctt ag 732 18 243 PRT Homo sapiens 18 Met Arg Pro Leu Leu Val Leu Leu Leu Leu Gly Leu Ala Ala Gly Ser 1 5 10 15 Pro Pro Leu Asp Asp Asn Lys Ile Pro Ser Leu Cys Pro Gly His Pro 20 25 30 Gly Leu Pro Gly Thr Pro Gly His His Gly Ser Gln Gly Leu Pro Gly 35 40 45 Arg Asp Gly Arg Asp Gly Arg Asp Gly Ala Pro Gly Ala Pro Gly Glu 50 55 60 Lys Gly Glu Gly Gly Arg Pro Gly Leu Pro Gly Pro Arg Gly Asp Pro 65 70 75 80 Gly Pro Arg Gly Glu Ala Gly Pro Ala Gly Pro Thr Gly Pro Ala Gly 85 90 95 Glu Cys Ser Val Pro Pro Arg Ser Ala Phe Ser Ala Lys Arg Ser Glu 100 105 110 Ser Arg Val Pro Pro Pro Ser Asp Ala Pro Leu Pro Phe Asp Arg Val 115 120 125 Leu Val Asn Glu Gln Gly His Tyr Asp Ala Val Thr Gly Lys Phe Thr 130 135 140 Cys Gln Val Pro Gly Val Tyr Tyr Phe Ala Val His Ala Thr Val Tyr 145 150 155 160 Arg Ala Ser Leu Gln Phe Asp Leu Val Lys Asn Gly Glu Ser Ile Ala 165 170 175 Ser Phe Phe Gln Phe Phe Gly Gly Trp Pro Lys Pro Ala Ser Leu Ser 180 185 190 Gly Gly Ala Met Val Arg Leu Glu Pro Glu Asp Gln Val Trp Val Gln 195 200 205 Val Gly Val Gly Asp Tyr Ile Gly Ile Tyr Ala Ser Ile Lys Thr Asp 210 215 220 Ser Thr Phe Ser Gly Phe Leu Val Tyr Ser Asp Trp His Ser Ser Pro 225 230 235 240 Val Phe Ala 19 732 DNA Mus musculus 19 atgaggccac ttcttgccct tctgcttctg ggtctggtgt caggctctcc tcctctggac 60 gacaacaaga tccccagcct gtgtcccggg cagcccggcc ttccaggcac accaggtcac 120 catggcagcc aaggcctgcc tggccgtgac ggcsgtgatg gccgcgacgg tgcacccgga 180 gctccgggag agaaaggcga gggcgggaga ccgggactac ctggcccacg tggggagccc 240 gggccgcgtg gagaggcagg gcccatgggg gctatcgggc ctgcgggsga gtgctcggta 300 cccccacgat cagccttcag tgccaagcga tccgagagcc gggtacctcc gccagccgac 360 acacccctac ctttcgaccg tgtgctgcta aatgagcagg gccatttcga ccccactact 420 ggcaagttca cctgccaagt gcctggcgtc tactactttg ctgtgcacgc cactgtctac 480 cgggccagct tgcagtttga tcttgtcaaa aacgggcagt ccatcgcctc tttcttccag 540 tattttgggg ggtggcccaa gccagcctcg ctctcagggg gtgcgatggt aaggctagaa 600 cctgaggacc aggtgtgggt gcaggtgggc gtgggtgatt acattggcat ctatgccagc 660 atcaagacag acagtacctt ctctggattt ctcgtctatt ctgactggca cagctcccca 720 gtcttcgctt aa 732 20 243 PRT Mus musculus MISC_FEATURE (52)..(52) unsure 20 Met Arg Pro Leu Leu Ala Leu Leu Leu Leu Gly Leu Val Ser Gly Ser 1 5 10 15 Pro Pro Leu Asp Asp Asn Lys Ile Pro Ser Leu Cys Pro Gly Gln Pro 20 25 30 Gly Leu Pro Gly Thr Pro Gly His His Gly Ser Gln Gly Leu Pro Gly 35 40 45 Arg Asp Gly Xaa Asp Gly Arg Asp Gly Ala Pro Gly Ala Pro Gly Glu 50 55 60 Lys Gly Glu Gly Gly Arg Pro Gly Leu Pro Gly Pro Arg Gly Glu Pro 65 70 75 80 Gly Pro Arg Gly Glu Ala Gly Pro Met Gly Ala Ile Gly Pro Ala Gly 85 90 95 Glu Cys Ser Val Pro Pro Arg Ser Ala Phe Ser Ala Lys Arg Ser Glu 100 105 110 Ser Arg Val Pro Pro Pro Ala Asp Thr Pro Leu Pro Phe Asp Arg Val 115 120 125 Leu Leu Asn Glu Gln Gly His Phe Asp Pro Thr Thr Gly Lys Phe Thr 130 135 140 Cys Gln Val Pro Gly Val Tyr Tyr Phe Ala Val His Ala Thr Val Tyr 145 150 155 160 Arg Ala Ser Leu Gln Phe Asp Leu Val Lys Asn Gly Gln Ser Ile Ala 165 170 175 Ser Phe Phe Gln Tyr Phe Gly Gly Trp Pro Lys Pro Ala Ser Leu Ser 180 185 190 Gly Gly Ala Met Val Arg Leu Glu Pro Glu Asp Gln Val Trp Val Gln 195 200 205 Val Gly Val Gly Asp Tyr Ile Gly Ile Tyr Ala Ser Ile Lys Thr Asp 210 215 220 Ser Thr Phe Ser Gly Phe Leu Val Tyr Ser Asp Trp His Ser Ser Pro 225 230 235 240 Val Phe Ala 21 2850 DNA Homo sapiens 21 atgatcctga gcttgctgtt cagccttggg ggccccctgg gctgggggct gctgggggca 60 tgggcccagg cttccagtac tagcctctct gatctgcaga gctccaggac acctggggtc 120 tggaaggcag aggctgagga caccagcaag gaccccgttg gacgtaactg gtgcccctac 180 ccaatgtcca agctggtcac cttactagct ctttgcaaaa cagagaaatt cctcatccac 240 tcgcagcagc cgtgtccgca gggagctcca gactgccaga aagtcaaagt catgtaccgc 300 atggcccaca agccagtgta ccaggtcaag cagaaggtgc tgacctcttt ggcctggagg 360 tgctgccctg gctacacggg ccccaactgc gagcaccacg attccatggc aatccctgag 420 cctgcagatc ctggtgacag ccaccaggaa cctcaggatg gaccagtcag cttcaaacct 480 ggccaccttg ctgcagtgat caatgaggtt gaggtgcaac aggaacagca ggaacatctg 540 ctgggagatc tccagaatga tgtgcaccgg gtggcagaca gcctgccagg cctgtggaaa 600 gccctgcctg gtaacctcac agctgcagtg atggaagcaa atcaaacagg gcacgagttc 660 cctgatagat ccttggagca ggtgctgcta ccccacgtgg acaccttcct acaagtgcat 720 ttcagcccca tctggaggag ctttaaccaa agcctgcaca gccttaccca ggccataaga 780 aacctgtctc ttgacgtgga ggccaaccgc caggccatct ccagagtcca ggacagtgcc 840 gtggccaggg ctgacttcca ggagcttggt gccaaatttg aggccaaggt ccaggagaac 900 actcagagag tgggtcagct gcgacaggac gtggaggacc gcctgcacgc ccagcacttt 960 accctgcacc gctcgatctc agagctccaa gccgatgtgg acaccaaatt gaagaggctg 1020 cacaaggctc aggaggcccc agggaccaat ggcagtctgg tgttggcaac gcctggggct 1080 ggggcaaggc ctgagccgga cagcctgcag gccaggctgg gccagctgca gaggaacctc 1140 tcagagctgc acatgaccac ggcccgcagg gaggaggagt tgcagtacac cctggaggac 1200 atgagggcca ccctgacccg gcacgtggat gagatcaagg aactgtactc cgaatcggac 1260 gagactttcg atcagattag caaggtggag cggcaggtgg aggagctgca ggtgaaccac 1320 acggcgctcc gtgagctgcg cgtgatcctg atggagaagt ctctgatcat ggaggagaac 1380 aaggaggagg tggagcggca gctcctggag ctcaacctca cgctgcagca cctgcagggt 1440 ggccatgccg acctcatcaa gtacgtgaag gactgcaatt gccagaagct ctatttagac 1500 ctggacgtca tccgggaggg ccagagggac gccacgcgtg ccctggagga gacccaggtg 1560 agcctggacg agcggcggca gctggacggc tcctccctgc aggccctgca gaacgccgtg 1620 gacgccgtgt cgctggccgt ggacgcgcac aaagcggagg gcgagcgggc gcgggcggcc 1680 acgtcgcggc tccggagcca agtgcaggcg ctggatgacg aggtgggcgc gctgaaggcg 1740 gccgcggccg aggcccgcca cgaggtgcgc cagctgcaca gcgccttcgc cgccctgctg 1800 gaggacgcgc tgcggcacga ggcggtgctg gccgcgctct tcggggagga ggtgctggag 1860 gagatgtctg agcagacgcc gggaccgctg cccctgagct acgagcagat ccgcgtggcc 1920 ctgcaggacg ccgctagcgg gctgcaggag caggcgctcg gctgggacga gctggccgcc 1980 cgagtgacgg ccctggagca ggcctcggag cccccgcggc cggcagagca cctggagccc 2040 agccacgacg cgggccgcga ggaggccgcc accaccgccc tggccgggct ggcgcgggag 2100 ctccagagcc tgagcaacga cgtcaagaat gtcgggcggt gctgcgaggc cgaggccggg 2160 gccggggccg cctccctcaa cgcctccctt gacggcctcc acaacgcact cttcgccact 2220 cagcgcagct tggagcagca ccagcggctc ttccacagcc tctttgggaa cttccaaggg 2280 ctcatggaag ccaacgtcag cctggacctg gggaagctgc agaccatgct gagcaggaaa 2340 gggaagaagc agcagaaaga cctggaagct ccccggaaga gggacaagaa ggaagcggag 2400 cctttggtgg acatacgggt cacagggcct gtgccaggtg ccttgggcgc ggcgctctgg 2460 gaggcaggat cccctgtggc cttctatgcc agcttttcag aagggacgsc tgccctgcag 2520 acagtgaagt tcaacaccac atacatcaac attggcagca gctacttccc tgaacatggc 2580 tacttccgag cccctgagcg tggtgtctac ctgtttgcag tgagcgttga atttggccca 2640 gggccaggca ccgggcagct ggtgtttgga ggtcaccatc ggactccagt ctgtaccact 2700 gggcagggga gtggaagcac agcaacggtc tttgccatgg ctgagctgca gaagggtgag 2760 cgagtatggt ttgagttaac ccagggatca ataacaaaga gaagcctgtc gggcactgca 2820 tttgggggct tcctgatgtt taagacctga 2850 22 949 PRT Homo sapiens 22 Met Ile Leu Ser Leu Leu Phe Ser Leu Gly Gly Pro Leu Gly Trp Gly 1 5 10 15 Leu Leu Gly Ala Trp Ala Gln Ala Ser Ser Thr Ser Leu Ser Asp Leu 20 25 30 Gln Ser Ser Arg Thr Pro Gly Val Trp Lys Ala Glu Ala Glu Asp Thr 35 40 45 Ser Lys Asp Pro Val Gly Arg Asn Trp Cys Pro Tyr Pro Met Ser Lys 50 55 60 Leu Val Thr Leu Leu Ala Leu Cys Lys Thr Glu Lys Phe Leu Ile His 65 70 75 80 Ser Gln Gln Pro Cys Pro Gln Gly Ala Pro Asp Cys Gln Lys Val Lys 85 90 95 Val Met Tyr Arg Met Ala His Lys Pro Val Tyr Gln Val Lys Gln Lys 100 105 110 Val Leu Thr Ser Leu Ala Trp Arg Cys Cys Pro Gly Tyr Thr Gly Pro 115 120 125 Asn Cys Glu His His Asp Ser Met Ala Ile Pro Glu Pro Ala Asp Pro 130 135 140 Gly Asp Ser His Gln Glu Pro Gln Asp Gly Pro Val Ser Phe Lys Pro 145 150 155 160 Gly His Leu Ala Ala Val Ile Asn Glu Val Glu Val Gln Gln Glu Gln 165 170 175 Gln Glu His Leu Leu Gly Asp Leu Gln Asn Asp Val His Arg Val Ala 180 185 190 Asp Ser Leu Pro Gly Leu Trp Lys Ala Leu Pro Gly Asn Leu Thr Ala 195 200 205 Ala Val Met Glu Ala Asn Gln Thr Gly His Glu Phe Pro Asp Arg Ser 210 215 220 Leu Glu Gln Val Leu Leu Pro His Val Asp Thr Phe Leu Gln Val His 225 230 235 240 Phe Ser Pro Ile Trp Arg Ser Phe Asn Gln Ser Leu His Ser Leu Thr 245 250 255 Gln Ala Ile Arg Asn Leu Ser Leu Asp Val Glu Ala Asn Arg Gln Ala 260 265 270 Ile Ser Arg Val Gln Asp Ser Ala Val Ala Arg Ala Asp Phe Gln Glu 275 280 285 Leu Gly Ala Lys Phe Glu Ala Lys Val Gln Glu Asn Thr Gln Arg Val 290 295 300 Gly Gln Leu Arg Gln Asp Val Glu Asp Arg Leu His Ala Gln His Phe 305 310 315 320 Thr Leu His Arg Ser Ile Ser Glu Leu Gln Ala Asp Val Asp Thr Lys 325 330 335 Leu Lys Arg Leu His Lys Ala Gln Glu Ala Pro Gly Thr Asn Gly Ser 340 345 350 Leu Val Leu Ala Thr Pro Gly Ala Gly Ala Arg Pro Glu Pro Asp Ser 355 360 365 Leu Gln Ala Arg Leu Gly Gln Leu Gln Arg Asn Leu Ser Glu Leu His 370 375 380 Met Thr Thr Ala Arg Arg Glu Glu Glu Leu Gln Tyr Thr Leu Glu Asp 385 390 395 400 Met Arg Ala Thr Leu Thr Arg His Val Asp Glu Ile Lys Glu Leu Tyr 405 410 415 Ser Glu Ser Asp Glu Thr Phe Asp Gln Ile Ser Lys Val Glu Arg Gln 420 425 430 Val Glu Glu Leu Gln Val Asn His Thr Ala Leu Arg Glu Leu Arg Val 435 440 445 Ile Leu Met Glu Lys Ser Leu Ile Met Glu Glu Asn Lys Glu Glu Val 450 455 460 Glu Arg Gln Leu Leu Glu Leu Asn Leu Thr Leu Gln His Leu Gln Gly 465 470 475 480 Gly His Ala Asp Leu Ile Lys Tyr Val Lys Asp Cys Asn Cys Gln Lys 485 490 495 Leu Tyr Leu Asp Leu Asp Val Ile Arg Glu Gly Gln Arg Asp Ala Thr 500 505 510 Arg Ala Leu Glu Glu Thr Gln Val Ser Leu Asp Glu Arg Arg Gln Leu 515 520 525 Asp Gly Ser Ser Leu Gln Ala Leu Gln Asn Ala Val Asp Ala Val Ser 530 535 540 Leu Ala Val Asp Ala His Lys Ala Glu Gly Glu Arg Ala Arg Ala Ala 545 550 555 560 Thr Ser Arg Leu Arg Ser Gln Val Gln Ala Leu Asp Asp Glu Val Gly 565 570 575 Ala Leu Lys Ala Ala Ala Ala Glu Ala Arg His Glu Val Arg Gln Leu 580 585 590 His Ser Ala Phe Ala Ala Leu Leu Glu Asp Ala Leu Arg His Glu Ala 595 600 605 Val Leu Ala Ala Leu Phe Gly Glu Glu Val Leu Glu Glu Met Ser Glu 610 615 620 Gln Thr Pro Gly Pro Leu Pro Leu Ser Tyr Glu Gln Ile Arg Val Ala 625 630 635 640 Leu Gln Asp Ala Ala Ser Gly Leu Gln Glu Gln Ala Leu Gly Trp Asp 645 650 655 Glu Leu Ala Ala Arg Val Thr Ala Leu Glu Gln Ala Ser Glu Pro Pro 660 665 670 Arg Pro Ala Glu His Leu Glu Pro Ser His Asp Ala Gly Arg Glu Glu 675 680 685 Ala Ala Thr Thr Ala Leu Ala Gly Leu Ala Arg Glu Leu Gln Ser Leu 690 695 700 Ser Asn Asp Val Lys Asn Val Gly Arg Cys Cys Glu Ala Glu Ala Gly 705 710 715 720 Ala Gly Ala Ala Ser Leu Asn Ala Ser Leu Asp Gly Leu His Asn Ala 725 730 735 Leu Phe Ala Thr Gln Arg Ser Leu Glu Gln His Gln Arg Leu Phe His 740 745 750 Ser Leu Phe Gly Asn Phe Gln Gly Leu Met Glu Ala Asn Val Ser Leu 755 760 765 Asp Leu Gly Lys Leu Gln Thr Met Leu Ser Arg Lys Gly Lys Lys Gln 770 775 780 Gln Lys Asp Leu Glu Ala Pro Arg Lys Arg Asp Lys Lys Glu Ala Glu 785 790 795 800 Pro Leu Val Asp Ile Arg Val Thr Gly Pro Val Pro Gly Ala Leu Gly 805 810 815 Ala Ala Leu Trp Glu Ala Gly Ser Pro Val Ala Phe Tyr Ala Ser Phe 820 825 830 Ser Glu Gly Thr Ala Ala Leu Gln Thr Val Lys Phe Asn Thr Thr Tyr 835 840 845 Ile Asn Ile Gly Ser Ser Tyr Phe Pro Glu His Gly Tyr Phe Arg Ala 850 855 860 Pro Glu Arg Gly Val Tyr Leu Phe Ala Val Ser Val Glu Phe Gly Pro 865 870 875 880 Gly Pro Gly Thr Gly Gln Leu Val Phe Gly Gly His His Arg Thr Pro 885 890 895 Val Cys Thr Thr Gly Gln Gly Ser Gly Ser Thr Ala Thr Val Phe Ala 900 905 910 Met Ala Glu Leu Gln Lys Gly Glu Arg Val Trp Phe Glu Leu Thr Gln 915 920 925 Gly Ser Ile Thr Lys Arg Ser Leu Ser Gly Thr Ala Phe Gly Gly Phe 930 935 940 Leu Met Phe Lys Thr 945 23 1974 DNA Mus musculus misc_feature (1288)..(1290) unsure 23 atgatcccga cactgctgct gggctttggg gtgtacctga gctggggact gctagggtcc 60 tgggcacagg accccggtac caagttctcc catctcaata ggcccggcat gcctgaaggc 120 tggagactag gggctgagga taccagcaga gaccccatca gacggaactg gtgtccttac 180 cagaagtcca ggctggtcac ctttgtagct gcttgcaaaa cagagaaatt cctggtccat 240 tcacagcagc catgtccaca gggagcccct gactgccagg gagtcagagt catgtatcga 300 gtggcccaga agccagtgta ccaggtccag cagaaggtgc tgatctctgt ggactggcgg 360 tgctgcccag ggttccaggg accagactgc caggaccaca atcccacagc aaaccctgag 420 cccacagagc caagtggtaa actccaggag acttgggact cgatggatgg ctttgaactt 480 ggtcaccctg tcccagagtt taatgagatt aaggtgccac aggaacaaca ggaaaacctg 540 cttcaaaatc tccagaatga tgcccagtca gtagaagatg gctttccagg ctcttgggaa 600 gccccaccca gcaacctcac agatgagatg acagaagcca atctaacaga attcgagttt 660 cctggcagga catcagagca cctgctgcag ccccatattg atgcattcct gaaagcacac 720 ttcagtccca tctggaagaa cttcaacgac agcttgcaca gcctctccca ggccatcaga 780 aacttgtctc ttgatgtgga ggccaatcac caggccatca agatgatcca ggagggcaca 840 gtggctaggg ctgacttcca agagcttggt gccaagtttg aggccaaggt ccagcagaat 900 agccagagac tgggccaact gtggcaggat gtggaggacc agctgcatgc ccagcgccga 960 tcggtgcatc atgccctctc tgaggtccag gctgaggtga gcaccaagtt aaagcagctt 1020 gtcaaggctc aggaacttcc aggggccaat ggcagcctgg tggtggtatc tgcagcagcg 1080 gcagcaaggc cagagccaga gagcctgcag gccaggctag ggcagctgca gagaaacctc 1140 tctgctctgc acatggtcac tagccagagg gaggaggagt tgcagagcac cctcaagaac 1200 atggacagcg tcctgaagca gcacgccgaa gagatcaagg agctctattc tgaatcggat 1260 gagaccttcg accagatcag caaggtannn cagtgctgtg aggcctcntg ggctgcctca 1320 atcaatagct cccttgaaga cctacacagc atgctcttcg acacccagca cggcttgaga 1380 cagcaccggc agctcttcca caacctcttc cagaacttcc aaggtctggt ggcaagcaac 1440 atcagcctag acttggggaa gctgcaggcc atgttgagta agaaagataa gaagcaaccg 1500 agaggcccag gagaatcccg gaagagggat aagaagcaag tggtgatgtc tacagacgca 1560 cacgccaaag gtctggagct ctgggagaca ggctcccctg tggccttcta tgccggttct 1620 tcagaagggg ccactgctct gcagatggtg aagttcaaca ccacatccat caatgtgggc 1680 agcagctact ttcctgaaca tggctacttc cgagctccca aacgtggcat ctacttattt 1740 gctgtgagca ttacatttgg cccaggccca ggaatggggc agctggtatt tgaaggtcat 1800 caccgggttc cagtctacag tacggaacag aggggtggga gcacagccac cacttttgct 1860 atggtagagc tgcaaaaggg tgagagagcg tggtttgagt tagtccaagg gtcagcaacc 1920 aaagggagcc gaccaggcac tgcatttggg ggcttcctga tgttcaagac ctga 1974 24 657 PRT Mus musculus MISC_FEATURE (430)..(430) unsure 24 Met Ile Pro Thr Leu Leu Leu Gly Phe Gly Val Tyr Leu Ser Trp Gly 1 5 10 15 Leu Leu Gly Ser Trp Ala Gln Asp Pro Gly Thr Lys Phe Ser His Leu 20 25 30 Asn Arg Pro Gly Met Pro Glu Gly Trp Arg Leu Gly Ala Glu Asp Thr 35 40 45 Ser Arg Asp Pro Ile Arg Arg Asn Trp Cys Pro Tyr Gln Lys Ser Arg 50 55 60 Leu Val Thr Phe Val Ala Ala Cys Lys Thr Glu Lys Phe Leu Val His 65 70 75 80 Ser Gln Gln Pro Cys Pro Gln Gly Ala Pro Asp Cys Gln Gly Val Arg 85 90 95 Val Met Tyr Arg Val Ala Gln Lys Pro Val Tyr Gln Val Gln Gln Lys 100 105 110 Val Leu Ile Ser Val Asp Trp Arg Cys Cys Pro Gly Phe Gln Gly Pro 115 120 125 Asp Cys Gln Asp His Asn Pro Thr Ala Asn Pro Glu Pro Thr Glu Pro 130 135 140 Ser Gly Lys Leu Gln Glu Thr Trp Asp Ser Met Asp Gly Phe Glu Leu 145 150 155 160 Gly His Pro Val Pro Glu Phe Asn Glu Ile Lys Val Pro Gln Glu Gln 165 170 175 Gln Glu Asn Leu Leu Gln Asn Leu Gln Asn Asp Ala Gln Ser Val Glu 180 185 190 Asp Gly Phe Pro Gly Ser Trp Glu Ala Pro Pro Ser Asn Leu Thr Asp 195 200 205 Glu Met Thr Glu Ala Asn Leu Thr Glu Phe Glu Phe Pro Gly Arg Thr 210 215 220 Ser Glu His Leu Leu Gln Pro His Ile Asp Ala Phe Leu Lys Ala His 225 230 235 240 Phe Ser Pro Ile Trp Lys Asn Phe Asn Asp Ser Leu His Ser Leu Ser 245 250 255 Gln Ala Ile Arg Asn Leu Ser Leu Asp Val Glu Ala Asn His Gln Ala 260 265 270 Ile Lys Met Ile Gln Glu Gly Thr Val Ala Arg Ala Asp Phe Gln Glu 275 280 285 Leu Gly Ala Lys Phe Glu Ala Lys Val Gln Gln Asn Ser Gln Arg Leu 290 295 300 Gly Gln Leu Trp Gln Asp Val Glu Asp Gln Leu His Ala Gln Arg Arg 305 310 315 320 Ser Val His His Ala Leu Ser Glu Val Gln Ala Glu Val Ser Thr Lys 325 330 335 Leu Lys Gln Leu Val Lys Ala Gln Glu Leu Pro Gly Ala Asn Gly Ser 340 345 350 Leu Val Val Val Ser Ala Ala Ala Ala Ala Arg Pro Glu Pro Glu Ser 355 360 365 Leu Gln Ala Arg Leu Gly Gln Leu Gln Arg Asn Leu Ser Ala Leu His 370 375 380 Met Val Thr Ser Gln Arg Glu Glu Glu Leu Gln Ser Thr Leu Lys Asn 385 390 395 400 Met Asp Ser Val Leu Lys Gln His Ala Glu Glu Ile Lys Glu Leu Tyr 405 410 415 Ser Glu Ser Asp Glu Thr Phe Asp Gln Ile Ser Lys Val Xaa Gln Cys 420 425 430 Cys Glu Ala Ser Trp Ala Ala Ser Ile Asn Ser Ser Leu Glu Asp Leu 435 440 445 His Ser Met Leu Phe Asp Thr Gln His Gly Leu Arg Gln His Arg Gln 450 455 460 Leu Phe His Asn Leu Phe Gln Asn Phe Gln Gly Leu Val Ala Ser Asn 465 470 475 480 Ile Ser Leu Asp Leu Gly Lys Leu Gln Ala Met Leu Ser Lys Lys Asp 485 490 495 Lys Lys Gln Pro Arg Gly Pro Gly Glu Ser Arg Lys Arg Asp Lys Lys 500 505 510 Gln Val Val Met Ser Thr Asp Ala His Ala Lys Gly Leu Glu Leu Trp 515 520 525 Glu Thr Gly Ser Pro Val Ala Phe Tyr Ala Gly Ser Ser Glu Gly Ala 530 535 540 Thr Ala Leu Gln Met Val Lys Phe Asn Thr Thr Ser Ile Asn Val Gly 545 550 555 560 Ser Ser Tyr Phe Pro Glu His Gly Tyr Phe Arg Ala Pro Lys Arg Gly 565 570 575 Ile Tyr Leu Phe Ala Val Ser Ile Thr Phe Gly Pro Gly Pro Gly Met 580 585 590 Gly Gln Leu Val Phe Glu Gly His His Arg Val Pro Val Tyr Ser Thr 595 600 605 Glu Gln Arg Gly Gly Ser Thr Ala Thr Thr Phe Ala Met Val Glu Leu 610 615 620 Gln Lys Gly Glu Arg Ala Trp Phe Glu Leu Val Gln Gly Ser Ala Thr 625 630 635 640 Lys Gly Ser Arg Pro Gly Thr Ala Phe Gly Gly Phe Leu Met Phe Lys 645 650 655 Thr 25 2763 DNA Homo sapiens 25 atgtaccgcc gcttcctccg ccctcgctac cgtgtggcct acaagacagt gaccgacatg 60 gagtggaggt gctgtcaggg ttatgggggc gatgactgtg ctgagagtcc cgctccagcg 120 ctggggcctg cgtcttccac accacggccc ctggcccggc ctgcccgccc caacctctct 180 ggctccagtg caggcagccc cctcagtgga ctggggggag aaggtcctgg ggagtcagag 240 aaggtgcagc agctggagga acaggtgcag agcctgacca aggagctgca aggcctgcgg 300 ggcgtcctgc aaggactgag cgggcgcctg gcagaggatg tgcagagggc tgtggagacg 360 gccttcaacg ggaggcagca gccagctgac gcggctgccc gccctggggt gcatgaaacc 420 ctcaatgaga tccagcacca gctgcagctc ctggacaccc gcgtctccac ccacgaccag 480 gagctgggtc acctcaacaa ccatcatggc ggcagcagca gcagtggggg cagcagggcc 540 ccagccccag cctcagcccc tccgggcccc agtgaggagc tgctgcggca gctggagcag 600 cggttgcagg agtcctgctc cgtgtgcctg gccgggctag atggcttccg ccggcagcag 660 caggaggaca gggagcggct gcgagcgatg gagaagctgc tggcctcggt ggaggagcgg 720 caacggcacc tcgcagggct ggcggtgggc cgcaggcccc ctcaggaatg ctgctctcca 780 gagctgggcc ggcgactggc agagctggag cgcaggctgg atgtcgtggc cggctcagtg 840 acagtgctga gtgggcggcg aggcacagag ctgggaggag ccgcggggca gggaggccac 900 cccccaggct acaccagctt ggcctcccgc ctgtctcgcc tggaggaccg cttcaactcc 960 accctgggcc cttcggagga gcaggaggag agctggcctg gggctcctgg ggggctgagc 1020 cactggctgc ctgctgcccg gggccgacta gagcagttgg gggggctgct ggccaatgtg 1080 agcggggagc tgggggggcg gttggatctg ttggaggagc aggtggcagg ggccatgcag 1140 gcatgcgggc agctctgctc tggggcccct ggggagcagg actctcaagt cagcgagatc 1200 ctcagtgcct tggagcgcag ggtgctggac agtgaggggc agctgcggct ggtgggctcc 1260 ggcctgcaca cggtggaagc agcgggggag gcccggcagg ccacgctgga gggattacaa 1320 gaggttgtgg gccggctcca ggatcgtgtg gatgcccagg atgagacagc tgcagagttc 1380 acactacggc tgaatctcac tgcggcccgg ctaggccaac tggaggggct gctgcaggcc 1440 catggggatg agggctgtgg ggcctgtggc ggagtccaag aggaactagg ccgccttcgg 1500 gatggtgtgg agcgctgctc ctgccccctg ttgcctcctc ggggtcctgg ggctggtcca 1560 ggtgttgggg gcccaagccg tgggcccctg gacggcttca gcgtgtttgg gggcagctca 1620 ggctcagccc tgcaggccct gcaaggagag ctctctgagg ttattctcag cttcagctcc 1680 ctcaatgact cactgaatga gctccagacc actgtggagg gccagggcgc tgatctggct 1740 gacctggggg caaccaagga ccgtatcatt tctgagatta acaggctgca gcaggaggcc 1800 acagagcatg ctacagagag tgaagagcgc ttccgaggcc tagaggaggg acaagcacag 1860 gccggccagt gccccagctt agaggggcga ttgggccgtc ttgagggtgt ctgtgaacgg 1920 ttggacactg tggctggggg actgcagggc ctgcgcgagg gcctttccag acacgtggct 1980 gggctctggg ctgggctccg ggaaaccaac accaccagcc agatgcaggc agccctgctg 2040 gagaagctgg tcgggggaca ggcgggcctg ggcaggcggc tgggtgccct taacagctcc 2100 ctgcagctcc tggaggaccg tctgcaccag ctcagcctga aggacctcac tgggcctgca 2160 ggagaggctg ggcccccagg gcctcctggg ctgcagggac ccccaggccc tgctggacct 2220 ccaggatcac caggcaagga cgggcaagag ggccccatcg ggccaccagg tcctcaaggt 2280 gaacagggag tggagggggc accagcagcc cctgtgcccc aagtggcatt ttcagctgct 2340 ctgagtttgc cccggtctga accaggcacg gtccccttcg acagagtcct gctcaatgat 2400 ggaggctatt atgatccaga gacaggcgtg ttcacagcgc cactggctgg acgctacttg 2460 ctgagcgcgg tgctgactgg gcaccggcac gagaaagtgg aggccgtgct gtcccgctcc 2520 aaccagggcg tggcccgcgt agactccggt ggctacgagc ctgagggcct ggagaataag 2580 ccggtggccg agagccagcc cagcccgggc accctgggcg tcttcagcct catcctgccg 2640 ctgcaggccg gggacacggt ctgcgtcgac ctggtcatgg ggcagctggc gcactcggag 2700 gagccgctca ccatcttcag cggggccctg ctctatgggg acccagagct tgaacacgcg 2760 tag 2763 26 920 PRT Homo sapiens 26 Met Tyr Arg Arg Phe Leu Arg Pro Arg Tyr Arg Val Ala Tyr Lys Thr 1 5 10 15 Val Thr Asp Met Glu Trp Arg Cys Cys Gln Gly Tyr Gly Gly Asp Asp 20 25 30 Cys Ala Glu Ser Pro Ala Pro Ala Leu Gly Pro Ala Ser Ser Thr Pro 35 40 45 Arg Pro Leu Ala Arg Pro Ala Arg Pro Asn Leu Ser Gly Ser Ser Ala 50 55 60 Gly Ser Pro Leu Ser Gly Leu Gly Gly Glu Gly Pro Gly Glu Ser Glu 65 70 75 80 Lys Val Gln Gln Leu Glu Glu Gln Val Gln Ser Leu Thr Lys Glu Leu 85 90 95 Gln Gly Leu Arg Gly Val Leu Gln Gly Leu Ser Gly Arg Leu Ala Glu 100 105 110 Asp Val Gln Arg Ala Val Glu Thr Ala Phe Asn Gly Arg Gln Gln Pro 115 120 125 Ala Asp Ala Ala Ala Arg Pro Gly Val His Glu Thr Leu Asn Glu Ile 130 135 140 Gln His Gln Leu Gln Leu Leu Asp Thr Arg Val Ser Thr His Asp Gln 145 150 155 160 Glu Leu Gly His Leu Asn Asn His His Gly Gly Ser Ser Ser Ser Gly 165 170 175 Gly Ser Arg Ala Pro Ala Pro Ala Ser Ala Pro Pro Gly Pro Ser Glu 180 185 190 Glu Leu Leu Arg Gln Leu Glu Gln Arg Leu Gln Glu Ser Cys Ser Val 195 200 205 Cys Leu Ala Gly Leu Asp Gly Phe Arg Arg Gln Gln Gln Glu Asp Arg 210 215 220 Glu Arg Leu Arg Ala Met Glu Lys Leu Leu Ala Ser Val Glu Glu Arg 225 230 235 240 Gln Arg His Leu Ala Gly Leu Ala Val Gly Arg Arg Pro Pro Gln Glu 245 250 255 Cys Cys Ser Pro Glu Leu Gly Arg Arg Leu Ala Glu Leu Glu Arg Arg 260 265 270 Leu Asp Val Val Ala Gly Ser Val Thr Val Leu Ser Gly Arg Arg Gly 275 280 285 Thr Glu Leu Gly Gly Ala Ala Gly Gln Gly Gly His Pro Pro Gly Tyr 290 295 300 Thr Ser Leu Ala Ser Arg Leu Ser Arg Leu Glu Asp Arg Phe Asn Ser 305 310 315 320 Thr Leu Gly Pro Ser Glu Glu Gln Glu Glu Ser Trp Pro Gly Ala Pro 325 330 335 Gly Gly Leu Ser His Trp Leu Pro Ala Ala Arg Gly Arg Leu Glu Gln 340 345 350 Leu Gly Gly Leu Leu Ala Asn Val Ser Gly Glu Leu Gly Gly Arg Leu 355 360 365 Asp Leu Leu Glu Glu Gln Val Ala Gly Ala Met Gln Ala Cys Gly Gln 370 375 380 Leu Cys Ser Gly Ala Pro Gly Glu Gln Asp Ser Gln Val Ser Glu Ile 385 390 395 400 Leu Ser Ala Leu Glu Arg Arg Val Leu Asp Ser Glu Gly Gln Leu Arg 405 410 415 Leu Val Gly Ser Gly Leu His Thr Val Glu Ala Ala Gly Glu Ala Arg 420 425 430 Gln Ala Thr Leu Glu Gly Leu Gln Glu Val Val Gly Arg Leu Gln Asp 435 440 445 Arg Val Asp Ala Gln Asp Glu Thr Ala Ala Glu Phe Thr Leu Arg Leu 450 455 460 Asn Leu Thr Ala Ala Arg Leu Gly Gln Leu Glu Gly Leu Leu Gln Ala 465 470 475 480 His Gly Asp Glu Gly Cys Gly Ala Cys Gly Gly Val Gln Glu Glu Leu 485 490 495 Gly Arg Leu Arg Asp Gly Val Glu Arg Cys Ser Cys Pro Leu Leu Pro 500 505 510 Pro Arg Gly Pro Gly Ala Gly Pro Gly Val Gly Gly Pro Ser Arg Gly 515 520 525 Pro Leu Asp Gly Phe Ser Val Phe Gly Gly Ser Ser Gly Ser Ala Leu 530 535 540 Gln Ala Leu Gln Gly Glu Leu Ser Glu Val Ile Leu Ser Phe Ser Ser 545 550 555 560 Leu Asn Asp Ser Leu Asn Glu Leu Gln Thr Thr Val Glu Gly Gln Gly 565 570 575 Ala Asp Leu Ala Asp Leu Gly Ala Thr Lys Asp Arg Ile Ile Ser Glu 580 585 590 Ile Asn Arg Leu Gln Gln Glu Ala Thr Glu His Ala Thr Glu Ser Glu 595 600 605 Glu Arg Phe Arg Gly Leu Glu Glu Gly Gln Ala Gln Ala Gly Gln Cys 610 615 620 Pro Ser Leu Glu Gly Arg Leu Gly Arg Leu Glu Gly Val Cys Glu Arg 625 630 635 640 Leu Asp Thr Val Ala Gly Gly Leu Gln Gly Leu Arg Glu Gly Leu Ser 645 650 655 Arg His Val Ala Gly Leu Trp Ala Gly Leu Arg Glu Thr Asn Thr Thr 660 665 670 Ser Gln Met Gln Ala Ala Leu Leu Glu Lys Leu Val Gly Gly Gln Ala 675 680 685 Gly Leu Gly Arg Arg Leu Gly Ala Leu Asn Ser Ser Leu Gln Leu Leu 690 695 700 Glu Asp Arg Leu His Gln Leu Ser Leu Lys Asp Leu Thr Gly Pro Ala 705 710 715 720 Gly Glu Ala Gly Pro Pro Gly Pro Pro Gly Leu Gln Gly Pro Pro Gly 725 730 735 Pro Ala Gly Pro Pro Gly Ser Pro Gly Lys Asp Gly Gln Glu Gly Pro 740 745 750 Ile Gly Pro Pro Gly Pro Gln Gly Glu Gln Gly Val Glu Gly Ala Pro 755 760 765 Ala Ala Pro Val Pro Gln Val Ala Phe Ser Ala Ala Leu Ser Leu Pro 770 775 780 Arg Ser Glu Pro Gly Thr Val Pro Phe Asp Arg Val Leu Leu Asn Asp 785 790 795 800 Gly Gly Tyr Tyr Asp Pro Glu Thr Gly Val Phe Thr Ala Pro Leu Ala 805 810 815 Gly Arg Tyr Leu Leu Ser Ala Val Leu Thr Gly His Arg His Glu Lys 820 825 830 Val Glu Ala Val Leu Ser Arg Ser Asn Gln Gly Val Ala Arg Val Asp 835 840 845 Ser Gly Gly Tyr Glu Pro Glu Gly Leu Glu Asn Lys Pro Val Ala Glu 850 855 860 Ser Gln Pro Ser Pro Gly Thr Leu Gly Val Phe Ser Leu Ile Leu Pro 865 870 875 880 Leu Gln Ala Gly Asp Thr Val Cys Val Asp Leu Val Met Gly Gln Leu 885 890 895 Ala His Ser Glu Glu Pro Leu Thr Ile Phe Ser Gly Ala Leu Leu Tyr 900 905 910 Gly Asp Pro Glu Leu Glu His Ala 915 920 27 2416 DNA Mus musculus 27 aaaagcaggc tggtaccggt ccggaattcc cgggatatcg tcgacccacg cgtccggccc 60 gggcgtgcat gaaaccctca gtgagatcca gcagcagctg cagctcctgg acaaccgtgt 120 ctccactcat gaccaggagc tgggccacct taacaaccat cataatggag gccctggtgg 180 aggtggcagg gcctcaggcc ctgtcccagt tccttctggc cccagtgaag aactgttaag 240 gcagctggaa cggcagctgc aagagtcttg ctcagtgtgc ctgacggggc tggatggctt 300 ccgccagcag cagcaagagg atagggagcg gctgcgaacc ctggagaagc taatgtcctc 360 tatggaggag cggcagcaac agcttgtggg acctgccatg gccaggagac cccctcagga 420 atgctgcccc ccagagctgg gtcgacgagt gtctgagctg gagcgaaggc tagatgtagt 480 gactggctca ctgacagtgc taagtggacg cagaggttct gagcttggag gagcagctgg 540 gcaggggggc caccctccag gctacaccag cttggcctcc cgcctttctc gcctggagga 600 ccgcttcaac tctaccctag gtccctcaga ggagcaagag aagaactggc ctggaggacc 660 agggaggctg ggccactggt tgcctgctgc tccaggacgg ctagaaaagc tggagggact 720 actagccaat gtgagcaggg agctgggtgg ccgcatggat ctgctggaag agcaggtggc 780 aggggctgtt cggacttgtg ggcagatttg ctctggggca cccggggaac aggattctcg 840 ggtcaatgag atcctcagtg ccttggaacg cagggtgctg gacagcgagg gccggttaca 900 gctagtgggc tctggcttgc atgaagcaga ggcagcaggg gaggctcagc aggccgtgtt 960 ggagggactg caagggctcc tgagccggct tcgggagcgc atggatgcac aggaggagac 1020 tgcagcagaa atcttactgc gcctcaatct taccgcagcc cagctaagcc agctggaggg 1080 tctgctgcaa gcccgtgggg atgagggttg tggcgcctgt ggtggtgtcc aggaggagct 1140 gggccgcctt cgggatggtg tggaacgttg ctcctgccca ttgttacctc cacggggccc 1200 tggagctggc ccaggggttg ggggaccaag ccgtgggcct ctggatggtt tcagtgtgtt 1260 tgggggcagt tcaggctcag ccctccaggc ccttcaagga gaactctctg aggttattct 1320 caccttcagc tccctgaacg actcactcca cgagctccag accactgtgg agggtcaggg 1380 tgccgatctg gctgacctgg gggccaccaa ggacagcatc atctctgaaa tcaacagact 1440 acagcaggag gccacggagc acgtcacaga gagcgaggag cgcttccgag gcctggagga 1500 gggccaggca caggctggcc aatgccctag cttagagggg cgattaggcc gccttgaggg 1560 agtctgcgaa cgactggaca ccgtggcagg gggactacaa ggcctacgtg aaggcctctc 1620 cagacacgtg gctgggctct gggctgcagt acgggaaagc aacagcacca gcctgacaca 1680 ggccgccctg ctggagaagc tgctgggggg ccaggcaggc ctgggcaggc ggcttggtgc 1740 cctcaacaat tccctgctgc tcctggaaga ccgtctgcag caacttagcc taaaggactt 1800 cactggacct tcaggcaagg ctgggccccc agggcctccc gggctacaag ggccttcagg 1860 ccctgcagga cctccaggac ctcctggcaa agacggacaa cagggggcca ttggcccacc 1920 aggtcctcaa ggggagcagg gagcggaggg agcaccagca gcccctgtgc ctagggtagc 1980 attttcagct gccctgagtt tgccacggtc agaacctggc acagtcccct tcgacagagt 2040 cttgctcaat gatggaggct actatgaccc agagacaggt gtattcactg caccactggc 2100 tggacgctat ttgctgagcg ctgtacttac tgggcaccgg catgagaaag tggaagcagt 2160 attgtcacgc tccaacctgg gcgtggcccg catagactcg ggaggctatg aacccgaggg 2220 actggagaat aagcctgtgg ccgaaagtca gcccagccca ggcgctctgg gcgtcttcag 2280 cctcattctg ccactgcagg tcggagacac tgtctgcatc gacctggtca tggggcagct 2340 ggcacactcc gaggagccgc tcaccatctt cagcggagcc ctgctctacg aggacacaga 2400 gcttgaacag gtgtag 2416 28 804 PRT Mus musculus 28 Lys Ala Gly Trp Tyr Arg Ser Gly Ile Pro Gly Ile Ser Ser Thr His 1 5 10 15 Ala Ser Gly Pro Gly Val His Glu Thr Leu Ser Glu Ile Gln Gln Gln 20 25 30 Leu Gln Leu Leu Asp Asn Arg Val Ser Thr His Asp Gln Glu Leu Gly 35 40 45 His Leu Asn Asn His His Asn Gly Gly Pro Gly Gly Gly Gly Arg Ala 50 55 60 Ser Gly Pro Val Pro Val Pro Ser Gly Pro Ser Glu Glu Leu Leu Arg 65 70 75 80 Gln Leu Glu Arg Gln Leu Gln Glu Ser Cys Ser Val Cys Leu Thr Gly 85 90 95 Leu Asp Gly Phe Arg Gln Gln Gln Gln Glu Asp Arg Glu Arg Leu Arg 100 105 110 Thr Leu Glu Lys Leu Met Ser Ser Met Glu Glu Arg Gln Gln Gln Leu 115 120 125 Val Gly Pro Ala Met Ala Arg Arg Pro Pro Gln Glu Cys Cys Pro Pro 130 135 140 Glu Leu Gly Arg Arg Val Ser Glu Leu Glu Arg Arg Leu Asp Val Val 145 150 155 160 Thr Gly Ser Leu Thr Val Leu Ser Gly Arg Arg Gly Ser Glu Leu Gly 165 170 175 Gly Ala Ala Gly Gln Gly Gly His Pro Pro Gly Tyr Thr Ser Leu Ala 180 185 190 Ser Arg Leu Ser Arg Leu Glu Asp Arg Phe Asn Ser Thr Leu Gly Pro 195 200 205 Ser Glu Glu Gln Glu Lys Asn Trp Pro Gly Gly Pro Gly Arg Leu Gly 210 215 220 His Trp Leu Pro Ala Ala Pro Gly Arg Leu Glu Lys Leu Glu Gly Leu 225 230 235 240 Leu Ala Asn Val Ser Arg Glu Leu Gly Gly Arg Met Asp Leu Leu Glu 245 250 255 Glu Gln Val Ala Gly Ala Val Arg Thr Cys Gly Gln Ile Cys Ser Gly 260 265 270 Ala Pro Gly Glu Gln Asp Ser Arg Val Asn Glu Ile Leu Ser Ala Leu 275 280 285 Glu Arg Arg Val Leu Asp Ser Glu Gly Arg Leu Gln Leu Val Gly Ser 290 295 300 Gly Leu His Glu Ala Glu Ala Ala Gly Glu Ala Gln Gln Ala Val Leu 305 310 315 320 Glu Gly Leu Gln Gly Leu Leu Ser Arg Leu Arg Glu Arg Met Asp Ala 325 330 335 Gln Glu Glu Thr Ala Ala Glu Ile Leu Leu Arg Leu Asn Leu Thr Ala 340 345 350 Ala Gln Leu Ser Gln Leu Glu Gly Leu Leu Gln Ala Arg Gly Asp Glu 355 360 365 Gly Cys Gly Ala Cys Gly Gly Val Gln Glu Glu Leu Gly Arg Leu Arg 370 375 380 Asp Gly Val Glu Arg Cys Ser Cys Pro Leu Leu Pro Pro Arg Gly Pro 385 390 395 400 Gly Ala Gly Pro Gly Val Gly Gly Pro Ser Arg Gly Pro Leu Asp Gly 405 410 415 Phe Ser Val Phe Gly Gly Ser Ser Gly Ser Ala Leu Gln Ala Leu Gln 420 425 430 Gly Glu Leu Ser Glu Val Ile Leu Thr Phe Ser Ser Leu Asn Asp Ser 435 440 445 Leu His Glu Leu Gln Thr Thr Val Glu Gly Gln Gly Ala Asp Leu Ala 450 455 460 Asp Leu Gly Ala Thr Lys Asp Ser Ile Ile Ser Glu Ile Asn Arg Leu 465 470 475 480 Gln Gln Glu Ala Thr Glu His Val Thr Glu Ser Glu Glu Arg Phe Arg 485 490 495 Gly Leu Glu Glu Gly Gln Ala Gln Ala Gly Gln Cys Pro Ser Leu Glu 500 505 510 Gly Arg Leu Gly Arg Leu Glu Gly Val Cys Glu Arg Leu Asp Thr Val 515 520 525 Ala Gly Gly Leu Gln Gly Leu Arg Glu Gly Leu Ser Arg His Val Ala 530 535 540 Gly Leu Trp Ala Ala Val Arg Glu Ser Asn Ser Thr Ser Leu Thr Gln 545 550 555 560 Ala Ala Leu Leu Glu Lys Leu Leu Gly Gly Gln Ala Gly Leu Gly Arg 565 570 575 Arg Leu Gly Ala Leu Asn Asn Ser Leu Leu Leu Leu Glu Asp Arg Leu 580 585 590 Gln Gln Leu Ser Leu Lys Asp Phe Thr Gly Pro Ser Gly Lys Ala Gly 595 600 605 Pro Pro Gly Pro Pro Gly Leu Gln Gly Pro Ser Gly Pro Ala Gly Pro 610 615 620 Pro Gly Pro Pro Gly Lys Asp Gly Gln Gln Gly Ala Ile Gly Pro Pro 625 630 635 640 Gly Pro Gln Gly Glu Gln Gly Ala Glu Gly Ala Pro Ala Ala Pro Val 645 650 655 Pro Arg Val Ala Phe Ser Ala Ala Leu Ser Leu Pro Arg Ser Glu Pro 660 665 670 Gly Thr Val Pro Phe Asp Arg Val Leu Leu Asn Asp Gly Gly Tyr Tyr 675 680 685 Asp Pro Glu Thr Gly Val Phe Thr Ala Pro Leu Ala Gly Arg Tyr Leu 690 695 700 Leu Ser Ala Val Leu Thr Gly His Arg His Glu Lys Val Glu Ala Val 705 710 715 720 Leu Ser Arg Ser Asn Leu Gly Val Ala Arg Ile Asp Ser Gly Gly Tyr 725 730 735 Glu Pro Glu Gly Leu Glu Asn Lys Pro Val Ala Glu Ser Gln Pro Ser 740 745 750 Pro Gly Ala Leu Gly Val Phe Ser Leu Ile Leu Pro Leu Gln Val Gly 755 760 765 Asp Thr Val Cys Ile Asp Leu Val Met Gly Gln Leu Ala His Ser Glu 770 775 780 Glu Pro Leu Thr Ile Phe Ser Gly Ala Leu Leu Tyr Glu Asp Thr Glu 785 790 795 800 Leu Glu Gln Val 29 2235 DNA Homo sapiens 29 atggctgtgc tgcctggccc tctgcagctg ctgggagtgc tgcttaccat ttccctgagt 60 tccatcaggc tcattcaggc tggtgcctac tatgggatca agccgctgcc acctcaaatt 120 cctcctcaga tgccaccaca aattccacaa taccagcccc tgggtcagca agtacctcac 180 atgcctttgg ccaaagatgg ccttgccatg ggcaaggaga tgccccactt gcagtatggc 240 aaagagtatc cacacctacc ccaatatatg aaggaaattc aaccggcgcc aagaatgggc 300 aaggaagccg tacccaagaa aggcaaagaa ataccattag ccagtttacg aggggaacaa 360 ggtccccgtg gagagcctgg cccaagagga ccacctgggc cccctggttt accaggtcat 420 gggatacctg gaattaaagg aaaaccaggg ccacagggat atccaggagt tggaaagcca 480 ggtatgcctg gaatgccagg gaagccagga gccatgggca tgcctggggc aaaaggagaa 540 attggacaga aaggggaaat tgggcctatg gggatcccag gaccacaagg acctccaggg 600 cctcatggac ttcctggcat tgggaagcca ggtgggccag ggttaccagg gcaaccagga 660 ccaaagggtg atcgaggacc caaaggacta ccaggacctc aaggccttcg gggtcctaaa 720 ggagacaagg gcttcgggat gccaggtgcg ccaggtgtaa aggggcctcc agggatgcac 780 ggccctcccg gccctgttgg actgccagga gtgggcaaac caggagtgac aggcttccct 840 gggccccagg gccccctggg aaagccaggg gctccaggag aacctgggcc acaaggccct 900 attggggtac cgggggttca aggacctcct gggatacccg gaattggaaa gccaggccag 960 gatgggatcc caggccagcc aggatttcca ggtggcaaag gggagcaagg actgccaggg 1020 ctaccagggg ccccaggcct tccagggatt gggaaaccag gcttcccagg acccaaaggt 1080 gaccggggca tgggaggtgt tcctggggct cttggaccaa gaggggagaa aggaccaata 1140 ggttccccag gaataggggg ttctccagga gagccaggcc tgcctggaat cccaggtcct 1200 atgggccctc caggtgctat tggttttcct ggacccaaag gagaaggtgg gattgtaggg 1260 ccacaggggc caccaggtcc caagggtgag ccagggcttc aaggcttccc aggaaagcca 1320 ggtttccttg gtgaagtagg gcctcctggc atgaggggtt tcccaggtcc cataggcccc 1380 aagggggaac atgggcaaaa aggtgtacca ggactccctg gtgttccagg gcttctcgga 1440 cctaagggag aaccaggaat cccaggggat cagggtttac agggcccccc aggtatccca 1500 gggattgggg gccctagtgg ccccattgga ccacctggga ttccaggccc caaaggggag 1560 cctggcctcc cagggccccc tgggttccct ggtataggga aacccggagt ggcaggactt 1620 catggccccc cagggaagcc tggtgccctt ggtcctcaag gccagcctgg ccttccagga 1680 cccccaggcc ctccaggacc tccaggaccc ccagctgtga tgccccctac accaccaccc 1740 cagggagagt atctgccaga tatggggctg ggaattgatg gcgtgaaacc cccccatgcc 1800 tacggggcta agaaaggcaa gaatggaggg ccagcctatg agatgcctgc atttaccgcc 1860 gagctaaccg cacctttccc accggtgggg gccccagtga agtttaacaa actgctgtat 1920 aacggcagac agaactacaa cccgcagaca ggcatcttca cctgtgaggt ccctggtgtc 1980 tactactttg cataccacgt tcactgcaag gggggcaacg tgtgggttgc tctattcaag 2040 aacaacgagc ccgtgatgta cacgtacgac gagtacaaaa agggcttcct ggaccaggca 2100 tctgggagtg cagtgctgct gctcaggccc ggagaccggg tgttcctcca gatgccctca 2160 gaacaggctg caggactgta tgccgggcag tatgtccact cctccttttc aggatattta 2220 ttgtatccca tgtaa 2235 30 744 PRT Homo sapiens 30 Met Ala Val Leu Pro Gly Pro Leu Gln Leu Leu Gly Val Leu Leu Thr 1 5 10 15 Ile Ser Leu Ser Ser Ile Arg Leu Ile Gln Ala Gly Ala Tyr Tyr Gly 20 25 30 Ile Lys Pro Leu Pro Pro Gln Ile Pro Pro Gln Met Pro Pro Gln Ile 35 40 45 Pro Gln Tyr Gln Pro Leu Gly Gln Gln Val Pro His Met Pro Leu Ala 50 55 60 Lys Asp Gly Leu Ala Met Gly Lys Glu Met Pro His Leu Gln Tyr Gly 65 70 75 80 Lys Glu Tyr Pro His Leu Pro Gln Tyr Met Lys Glu Ile Gln Pro Ala 85 90 95 Pro Arg Met Gly Lys Glu Ala Val Pro Lys Lys Gly Lys Glu Ile Pro 100 105 110 Leu Ala Ser Leu Arg Gly Glu Gln Gly Pro Arg Gly Glu Pro Gly Pro 115 120 125 Arg Gly Pro Pro Gly Pro Pro Gly Leu Pro Gly His Gly Ile Pro Gly 130 135 140 Ile Lys Gly Lys Pro Gly Pro Gln Gly Tyr Pro Gly Val Gly Lys Pro 145 150 155 160 Gly Met Pro Gly Met Pro Gly Lys Pro Gly Ala Met Gly Met Pro Gly 165 170 175 Ala Lys Gly Glu Ile Gly Gln Lys Gly Glu Ile Gly Pro Met Gly Ile 180 185 190 Pro Gly Pro Gln Gly Pro Pro Gly Pro His Gly Leu Pro Gly Ile Gly 195 200 205 Lys Pro Gly Gly Pro Gly Leu Pro Gly Gln Pro Gly Pro Lys Gly Asp 210 215 220 Arg Gly Pro Lys Gly Leu Pro Gly Pro Gln Gly Leu Arg Gly Pro Lys 225 230 235 240 Gly Asp Lys Gly Phe Gly Met Pro Gly Ala Pro Gly Val Lys Gly Pro 245 250 255 Pro Gly Met His Gly Pro Pro Gly Pro Val Gly Leu Pro Gly Val Gly 260 265 270 Lys Pro Gly Val Thr Gly Phe Pro Gly Pro Gln Gly Pro Leu Gly Lys 275 280 285 Pro Gly Ala Pro Gly Glu Pro Gly Pro Gln Gly Pro Ile Gly Val Pro 290 295 300 Gly Val Gln Gly Pro Pro Gly Ile Pro Gly Ile Gly Lys Pro Gly Gln 305 310 315 320 Asp Gly Ile Pro Gly Gln Pro Gly Phe Pro Gly Gly Lys Gly Glu Gln 325 330 335 Gly Leu Pro Gly Leu Pro Gly Ala Pro Gly Leu Pro Gly Ile Gly Lys 340 345 350 Pro Gly Phe Pro Gly Pro Lys Gly Asp Arg Gly Met Gly Gly Val Pro 355 360 365 Gly Ala Leu Gly Pro Arg Gly Glu Lys Gly Pro Ile Gly Ser Pro Gly 370 375 380 Ile Gly Gly Ser Pro Gly Glu Pro Gly Leu Pro Gly Ile Pro Gly Pro 385 390 395 400 Met Gly Pro Pro Gly Ala Ile Gly Phe Pro Gly Pro Lys Gly Glu Gly 405 410 415 Gly Ile Val Gly Pro Gln Gly Pro Pro Gly Pro Lys Gly Glu Pro Gly 420 425 430 Leu Gln Gly Phe Pro Gly Lys Pro Gly Phe Leu Gly Glu Val Gly Pro 435 440 445 Pro Gly Met Arg Gly Phe Pro Gly Pro Ile Gly Pro Lys Gly Glu His 450 455 460 Gly Gln Lys Gly Val Pro Gly Leu Pro Gly Val Pro Gly Leu Leu Gly 465 470 475 480 Pro Lys Gly Glu Pro Gly Ile Pro Gly Asp Gln Gly Leu Gln Gly Pro 485 490 495 Pro Gly Ile Pro Gly Ile Gly Gly Pro Ser Gly Pro Ile Gly Pro Pro 500 505 510 Gly Ile Pro Gly Pro Lys Gly Glu Pro Gly Leu Pro Gly Pro Pro Gly 515 520 525 Phe Pro Gly Ile Gly Lys Pro Gly Val Ala Gly Leu His Gly Pro Pro 530 535 540 Gly Lys Pro Gly Ala Leu Gly Pro Gln Gly Gln Pro Gly Leu Pro Gly 545 550 555 560 Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Ala Val Met Pro Pro 565 570 575 Thr Pro Pro Pro Gln Gly Glu Tyr Leu Pro Asp Met Gly Leu Gly Ile 580 585 590 Asp Gly Val Lys Pro Pro His Ala Tyr Gly Ala Lys Lys Gly Lys Asn 595 600 605 Gly Gly Pro Ala Tyr Glu Met Pro Ala Phe Thr Ala Glu Leu Thr Ala 610 615 620 Pro Phe Pro Pro Val Gly Ala Pro Val Lys Phe Asn Lys Leu Leu Tyr 625 630 635 640 Asn Gly Arg Gln Asn Tyr Asn Pro Gln Thr Gly Ile Phe Thr Cys Glu 645 650 655 Val Pro Gly Val Tyr Tyr Phe Ala Tyr His Val His Cys Lys Gly Gly 660 665 670 Asn Val Trp Val Ala Leu Phe Lys Asn Asn Glu Pro Val Met Tyr Thr 675 680 685 Tyr Asp Glu Tyr Lys Lys Gly Phe Leu Asp Gln Ala Ser Gly Ser Ala 690 695 700 Val Leu Leu Leu Arg Pro Gly Asp Arg Val Phe Leu Gln Met Pro Ser 705 710 715 720 Glu Gln Ala Ala Gly Leu Tyr Ala Gly Gln Tyr Val His Ser Ser Phe 725 730 735 Ser Gly Tyr Leu Leu Tyr Pro Met 740 31 2232 DNA Mus musculus 31 atggctgtgc caccaggccc tctacagctg ctgggaatac tgttcatcat ttccctgaac 60 tctgtcagac tcattcaggc cggtgcctac tatggaatca agcctctgcc acctcaaatc 120 cctcctcaga taccaccaca aattccacag taccagccct tgggccagca agtccctcac 180 atgcctttgg gcaaagatgg cctttccatg ggcaaggaga tgcctcacat gcagtatggc 240 aaagagtacc catacctccc ccaatatatg aaggaaatcc cacctgtgcc aagaatgggc 300 aaggaagtgg tgcccaaaaa aggcaaagaa gtaccgttag ccagtttgcg cggagaacaa 360 ggtccccgtg gagaacctgg accaagagga ccacctgggc cgccaggttt accaggtcat 420 ggaatgcctg gaatcaaagg aaaaccaggg ccccagggat atccaggaat tggaaagccc 480 ggtatgcctg gaatgcctgg gaagccagga gccatgggaa tgccaggggc aaaaggcgaa 540 attggaccca aaggggaaat cggacctatg ggaatcccag ggccacaagg gcctccagga 600 cctcatggac ttcctggcat cgggaaaccg ggtgggccag ggttaccagg gcaaccagga 660 gcaaaaggtg agagggggcc caaaggacca ccaggacctc ccggccttca gggtcccaaa 720 ggagagaagg gcttcgggat gctgggcttg ccaggtctga agggtcctcc aggtatgcat 780 ggccctcctg gaccagttgg actaccggga gtaggaaaac caggagtgac aggctttcct 840 ggaccacagg gtcccctggg gaagccaggg cctccagggg aacctggacc acaaggcctt 900 attggtgtgc caggagttca aggacctcct gggatgcctg gagttggaaa gccaggtcag 960 gatggatccc gcggccaacc aggatttccg ggtggtaaag gggaacaagg attgccaggg 1020 ttgcctggac ccccaggcct cccaggggtc ggaaagccag gtttcccagg acccaaaggg 1080 caccggggta ttgggggtgt tcctggggtt cttgggccga gaggggaaaa aggacccatt 1140 ggtgctcctg gaatgggggg tccacctgga gagccaggcc tacccggtat cccgggtccc 1200 atgggccctc caggtgctat tggtttccct ggacccaaag gagaaggtgg agttgtagga 1260 ccacagggtc caccaggccc caagggagag cctggcctcc aaggcttccc tgggaagcca 1320 ggttttcttg gtgaagtagg tccccctggc atgaggggtt tgcctggtcc tataggacca 1380 aagggagaag gtggtcacaa agggttgcca gggcttcccg gtgttccagg gctgcttgga 1440 cccaaaggag aacctggcat acctggggat cagggtctac agggtccccc agggattcca 1500 gggatcgtag gacctagtgg ccctattgga ccccctggga ttccgggccc caaaggagaa 1560 ccaggcctcc cagggccccc tgggttccct ggtgtaggga agccaggagt agcaggactt 1620 catgggcccc cggggaaacc tggtgccctt ggtccccaag gccagcctgg ccttcctgga 1680 cccccaggtc ctccaggacc cccaggccct ccagctgtga tgcctacacc atcaccccag 1740 ggagagtatc tgccagatat gggactagga attgatgggg tgaaaactcc gcatgcctat 1800 gcgggcaaaa agggcaaaca cggagggcca gcctatgaga tgcctgcgtt tactgccgag 1860 ctgactgtac ctttcccacc ggtgggggcc ccagtgaagt ttgacaagct gctctacaac 1920 ggcagacaga actacaatcc gcagacaggc atcttcacct gtgaagtccc gggtgtctac 1980 tactttgctt atcatgttca ctgcaaggga ggcaacgtat gggttgctct cttcaagaac 2040 aacgagccca tgatgtacac atacgacgag tacaagaagg gctttctgga ccaagcatct 2100 ggaagcgcag tactgctttt ccttcccgga gaccaggtgt ttctccaaat cccttcagaa 2160 caggctgctg gactctatcc cgggcaatat gtccactcct ccttttcagg atatttattg 2220 tatcccatgt aa 2232 32 743 PRT Mus musculus 32 Met Ala Val Pro Pro Gly Pro Leu Gln Leu Leu Gly Ile Leu Phe Ile 1 5 10 15 Ile Ser Leu Asn Ser Val Arg Leu Ile Gln Ala Gly Ala Tyr Tyr Gly 20 25 30 Ile Lys Pro Leu Pro Pro Gln Ile Pro Pro Gln Ile Pro Pro Gln Ile 35 40 45 Pro Gln Tyr Gln Pro Leu Gly Gln Gln Val Pro His Met Pro Leu Gly 50 55 60 Lys Asp Gly Leu Ser Met Gly Lys Glu Met Pro His Met Gln Tyr Gly 65 70 75 80 Lys Glu Tyr Pro Tyr Leu Pro Gln Tyr Met Lys Glu Ile Pro Pro Val 85 90 95 Pro Arg Met Gly Lys Glu Val Val Pro Lys Lys Gly Lys Glu Val Pro 100 105 110 Leu Ala Ser Leu Arg Gly Glu Gln Gly Pro Arg Gly Glu Pro Gly Pro 115 120 125 Arg Gly Pro Pro Gly Pro Pro Gly Leu Pro Gly His Gly Met Pro Gly 130 135 140 Ile Lys Gly Lys Pro Gly Pro Gln Gly Tyr Pro Gly Ile Gly Lys Pro 145 150 155 160 Gly Met Pro Gly Met Pro Gly Lys Pro Gly Ala Met Gly Met Pro Gly 165 170 175 Ala Lys Gly Glu Ile Gly Pro Lys Gly Glu Ile Gly Pro Met Gly Ile 180 185 190 Pro Gly Pro Gln Gly Pro Pro Gly Pro His Gly Leu Pro Gly Ile Gly 195 200 205 Lys Pro Gly Gly Pro Gly Leu Pro Gly Gln Pro Gly Ala Lys Gly Glu 210 215 220 Arg Gly Pro Lys Gly Pro Pro Gly Pro Pro Gly Leu Gln Gly Pro Lys 225 230 235 240 Gly Glu Lys Gly Phe Gly Met Leu Gly Leu Pro Gly Leu Lys Gly Pro 245 250 255 Pro Gly Met His Gly Pro Pro Gly Pro Val Gly Leu Pro Gly Val Gly 260 265 270 Lys Pro Gly Val Thr Gly Phe Pro Gly Pro Gln Gly Pro Leu Gly Lys 275 280 285 Pro Gly Pro Pro Gly Glu Pro Gly Pro Gln Gly Leu Ile Gly Val Pro 290 295 300 Gly Val Gln Gly Pro Pro Gly Met Pro Gly Val Gly Lys Pro Gly Gln 305 310 315 320 Asp Gly Ser Arg Gly Gln Pro Gly Phe Pro Gly Gly Lys Gly Glu Gln 325 330 335 Gly Leu Pro Gly Leu Pro Gly Pro Pro Gly Leu Pro Gly Val Gly Lys 340 345 350 Pro Gly Phe Pro Gly Pro Lys Gly His Arg Gly Ile Gly Gly Val Pro 355 360 365 Gly Val Leu Gly Pro Arg Gly Glu Lys Gly Pro Ile Gly Ala Pro Gly 370 375 380 Met Gly Gly Pro Pro Gly Glu Pro Gly Leu Pro Gly Ile Pro Gly Pro 385 390 395 400 Met Gly Pro Pro Gly Ala Ile Gly Phe Pro Gly Pro Lys Gly Glu Gly 405 410 415 Gly Val Val Gly Pro Gln Gly Pro Pro Gly Pro Lys Gly Glu Pro Gly 420 425 430 Leu Gln Gly Phe Pro Gly Lys Pro Gly Phe Leu Gly Glu Val Gly Pro 435 440 445 Pro Gly Met Arg Gly Leu Pro Gly Pro Ile Gly Pro Lys Gly Glu Gly 450 455 460 Gly His Lys Gly Leu Pro Gly Leu Pro Gly Val Pro Gly Leu Leu Gly 465 470 475 480 Pro Lys Gly Glu Pro Gly Ile Pro Gly Asp Gln Gly Leu Gln Gly Pro 485 490 495 Pro Gly Ile Pro Gly Ile Val Gly Pro Ser Gly Pro Ile Gly Pro Pro 500 505 510 Gly Ile Pro Gly Pro Lys Gly Glu Pro Gly Leu Pro Gly Pro Pro Gly 515 520 525 Phe Pro Gly Val Gly Lys Pro Gly Val Ala Gly Leu His Gly Pro Pro 530 535 540 Gly Lys Pro Gly Ala Leu Gly Pro Gln Gly Gln Pro Gly Leu Pro Gly 545 550 555 560 Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Ala Val Met Pro Thr 565 570 575 Pro Ser Pro Gln Gly Glu Tyr Leu Pro Asp Met Gly Leu Gly Ile Asp 580 585 590 Gly Val Lys Thr Pro His Ala Tyr Ala Gly Lys Lys Gly Lys His Gly 595 600 605 Gly Pro Ala Tyr Glu Met Pro Ala Phe Thr Ala Glu Leu Thr Val Pro 610 615 620 Phe Pro Pro Val Gly Ala Pro Val Lys Phe Asp Lys Leu Leu Tyr Asn 625 630 635 640 Gly Arg Gln Asn Tyr Asn Pro Gln Thr Gly Ile Phe Thr Cys Glu Val 645 650 655 Pro Gly Val Tyr Tyr Phe Ala Tyr His Val His Cys Lys Gly Gly Asn 660 665 670 Val Trp Val Ala Leu Phe Lys Asn Asn Glu Pro Met Met Tyr Thr Tyr 675 680 685 Asp Glu Tyr Lys Lys Gly Phe Leu Asp Gln Ala Ser Gly Ser Ala Val 690 695 700 Leu Leu Phe Leu Pro Gly Asp Gln Val Phe Leu Gln Ile Pro Ser Glu 705 710 715 720 Gln Ala Ala Gly Leu Tyr Pro Gly Gln Tyr Val His Ser Ser Phe Ser 725 730 735 Gly Tyr Leu Leu Tyr Pro Met 740 33 618 DNA Homo sapiens 33 atgttgggag ccaagccaca ctggctacca ggtcccctac acagtcccgg gctgcccttg 60 gttctggtgc ttctggccct gggggccggg tgggcccagg aggggtcaga gcccgtcctg 120 ctggaggggg agtgcctggt ggtctgtgag cctggccgag ctgctgcagg ggggcccggg 180 ggagcagccc tgggagaggc accccctggg cgagtggcat ttgctgcggt ccgaagccac 240 caccatgagc cagcagggga aaccggcaat ggcaccagtg gggccatcta cttcgaccag 300 gtcctggtga acgagggcgg tggctttgac cgggcctctg gctccttcgt agcccctgtc 360 cggggtgtct acagcttccg gttccatgtg gtgaaggtgt acaaccgcca aactgtccag 420 gtgagcctga tgctgaacac gtggcctgtc atctcagcct ttgccaatga tcctgacgtg 480 acccgggagg cagccaccag ctctgtgcta ctgcccttgg accctgggga ccgagtgtct 540 ctgcgcctgc gtcgggggaa tctactgggt ggttggaaat actcaagttt ctctggcttc 600 ctcatcttcc ctctctga 618 34 205 PRT Homo sapiens 34 Met Leu Gly Ala Lys Pro His Trp Leu Pro Gly Pro Leu His Ser Pro 1 5 10 15 Gly Leu Pro Leu Val Leu Val Leu Leu Ala Leu Gly Ala Gly Trp Ala 20 25 30 Gln Glu Gly Ser Glu Pro Val Leu Leu Glu Gly Glu Cys Leu Val Val 35 40 45 Cys Glu Pro Gly Arg Ala Ala Ala Gly Gly Pro Gly Gly Ala Ala Leu 50 55 60 Gly Glu Ala Pro Pro Gly Arg Val Ala Phe Ala Ala Val Arg Ser His 65 70 75 80 His His Glu Pro Ala Gly Glu Thr Gly Asn Gly Thr Ser Gly Ala Ile 85 90 95 Tyr Phe Asp Gln Val Leu Val Asn Glu Gly Gly Gly Phe Asp Arg Ala 100 105 110 Ser Gly Ser Phe Val Ala Pro Val Arg Gly Val Tyr Ser Phe Arg Phe 115 120 125 His Val Val Lys Val Tyr Asn Arg Gln Thr Val Gln Val Ser Leu Met 130 135 140 Leu Asn Thr Trp Pro Val Ile Ser Ala Phe Ala Asn Asp Pro Asp Val 145 150 155 160 Thr Arg Glu Ala Ala Thr Ser Ser Val Leu Leu Pro Leu Asp Pro Gly 165 170 175 Asp Arg Val Ser Leu Arg Leu Arg Arg Gly Asn Leu Leu Gly Gly Trp 180 185 190 Lys Tyr Ser Ser Phe Ser Gly Phe Leu Ile Phe Pro Leu 195 200 205 35 639 DNA Mus musculus 35 acagaagaca ggaaaatctg tgagttacag aggcacctag caaggatggg gacggaatgg 60 cacaaaccca agctgtcctt ggccctggtg cttctgaccc tggaggctgg gtgggctcaa 120 gaagggtcag agcctgtcct actggagggg gagtgcctgg tggtctgtga gccaggccga 180 cctactgcag gaggacctgg gggtgcagcc ctgggagagg cacccccagg acgagtggcg 240 tttgctgcag tccgaagcca tcaccatgaa ccagcaggag aaaccggcaa cggtaccagt 300 ggtgccatct acttcgacca ggtactggtc aatgagggcg agggctttga tcggacctcg 360 ggctgcttcg tggcccctgt ccgtggagtc tacagcttcc gattccacgt ggtcaaggtg 420 tacaaccgcc aaactgtcca ggtgagtctg atgctgaaca catggccggt catctcagcc 480 tttgcaaatg accctgatgt gacccgagag gcagccacaa gctctgtgct gcttcccctg 540 gacccggggg accgtgtgtc cctgcgcctg cgtcggggga atcttctggg tggctggaag 600 tattcgagct tctcaggctt cctcatcttc ccactctga 639 36 213 PRT Mus musculus 36 Met Thr Glu Asp Arg Lys Ile Cys Glu Leu Gln Arg His Leu Ala Arg 1 5 10 15 Met Gly Thr Glu Trp His Lys Pro Lys Leu Ser Leu Ala Leu Val Leu 20 25 30 Leu Thr Leu Glu Ala Gly Trp Ala Gln Glu Gly Ser Glu Pro Val Leu 35 40 45 Leu Glu Gly Glu Cys Leu Val Val Cys Glu Pro Gly Arg Pro Thr Ala 50 55 60 Gly Gly Pro Gly Gly Ala Ala Leu Gly Glu Ala Pro Pro Gly Arg Val 65 70 75 80 Ala Phe Ala Ala Val Arg Ser His His His Glu Pro Ala Gly Glu Thr 85 90 95 Gly Asn Gly Thr Ser Gly Ala Ile Tyr Phe Asp Gln Val Leu Val Asn 100 105 110 Glu Gly Glu Gly Phe Asp Arg Thr Ser Gly Cys Phe Val Ala Pro Val 115 120 125 Arg Gly Val Tyr Ser Phe Arg Phe His Val Val Lys Val Tyr Asn Arg 130 135 140 Gln Thr Val Gln Val Ser Leu Met Leu Asn Thr Trp Pro Val Ile Ser 145 150 155 160 Ala Phe Ala Asn Asp Pro Asp Val Thr Arg Glu Ala Ala Thr Ser Ser 165 170 175 Val Leu Leu Pro Leu Asp Pro Gly Asp Arg Val Ser Leu Arg Leu Arg 180 185 190 Arg Gly Asn Leu Leu Gly Gly Trp Lys Tyr Ser Ser Phe Ser Gly Phe 195 200 205 Leu Ile Phe Pro Leu 210 

What is claimed is:
 1. An isolated nucleic acid encoding a polypeptide comprising SEQ ID NO:10 or 12, or an antigenic fragment thereof.
 2. An isolated nucleic acid which hybridizes to the nucleic acid of claim 1, under stringent conditions.
 3. The nucleic acid of claim 1 comprising SEQ ID NO:9 or
 11. 4. An expression or replicating vector comprising the nucleic acid of claim
 1. 5. A host cell comprising the expression or replicating vector of claim
 4. 6. An isolated polypeptide comprising SEQ ID NO:10 or 12, or an antigenic fragment thereof.
 7. The polypeptide of claim 6, further comprising a fusion polypeptide or peptide.
 8. A binding composition which specifically binds to the polypeptide of claim
 6. 9. The binding composition of claim 8, wherein the binding composition comprises an antigen binding site of an antibody.
 10. The binding composition of claim 9, wherein the binding composition is a polyclonal or monoclonal antibody.
 11. The binding composition of claim 9, wherein the binding composition is a humanized antibody.
 12. The binding composition of claim 9, wherein the binding composition is an Fab fragment, an F(ab′)₂ fragment, or an Fv fragment.
 13. The binding composition of claim 9, wherein the binding composition is detectably labeled.
 14. The binding composition of claim 8 in conjunction with an acceptable carrier.
 15. A kit comprising: a) the substantially pure polypeptide of claim 6; b) a binding composition which specifically binds the polypeptide; or c) a nucleic acid encoding the polypeptide.
 16. A method of producing a polypeptide comprising SEQ ID NO:10 or 12, or an antigenic fragment thereof, comprising: a) culturing the host cell of claim 5 under conditions suitable for expression of the polypeptide; and b) isolating or purifying the polypeptide.
 17. A method of modulating the activity of a cell comprising contacting the cell with the binding composition of claim
 8. 18. A method of treating a subject suffering from an inflammatory condition comprising administering an effective amount of an agonist or antagonist of the polypeptide of claim
 6. 19. The method of claim 18, wherein the agonist or antagonist is a binding composition which specifically binds to a polypeptide comprising SEQ ID NO:10 or 12, or an antigenic fragment thereof. 